Multidimensional penalized splines for survival models: illustration for net survival trend analyses.

BACKGROUND: In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. METHODS: The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990-2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. RESULTS: For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. CONCLUSIONS: MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study.

Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.

Factors influencing access to specialised haematology units during acute myeloblastic leukaemia patient care: A population-based study in France.

BACKGROUND: The excess mortality observed in Acute Myeloblastic Leukaemia (AML) patients, partly attributed to unequal access to curative treatments, could be linked to care pathways. METHODS: We included 1039 AML incident cases diagnosed between 2012-2016 from the 3 French blood cancer registries (3,625,400 inhabitants). We describe patients according to age, the medical entry unit and access to the specialised haematology unit (SHU) during follow-up. Multivariate logistic regression model was done to determine the association between covariables and access to SHU. A total of 713 patients (69%) had access to SHU during care. RESULTS: The most common care pathway concerned referral from the general practitioner to SHU, n = 459(44%). The univariate analysis observed a downward trend for the most deprived patients. Patients who consulted in SHU were younger (66 years vs. 83, p < 0.001), and 92% had access to cytogenetic analysis (vs. 54%, p < 0.001). They also had less poor prognosis AML-subtypes (AML-MRC, t-AML/MDS and AML-NOS) (38% vs. 69%); 77% with de novo AML (vs. 67%, p < 0.003)], more favourable cytogenetic prognostic status (23% vs. 6%, p < 0.001), less comorbidities (no comorbidity = 55% vs. 34%, p < 0.001) and treatments proposed were curative 68% (vs. 5.3%, p < 0.001). Factors limiting access to SHU were age over 80 years (OR, 0.14; 95% CI, 0.04-0.38), severe comorbidities (OR, 0.39; 95% CI, 0.21-0.69), emergency unit referral (OR, 0.28; 95% CI, 0.18-0.44) and non-SHU referral (OR, 0.12; 95% CI, 0.07-0.18). Consultation in an academic hospital increased access to SHU by 8.87 times (95% CI, 5.64-14.2). CONCLUSION: The high proportion of access to cytogenetic testing and curative treatment among patients admitted to SHU, and the importance of early treatment in AML underlines the importance of access to SHU for both diagnosis and treatment.

Additional value of chest CT AI-based quantification of lung involvement in predicting death and ICU admission for COVID-19 patients.

Objectives: We evaluated the contribution of lung lesion quantification on chest CT using a clinical Artificial Intelligence (AI) software in predicting death and intensive care units (ICU) admission for COVID-19 patients. Methods: For 349 patients with positive COVID-19-PCR test that underwent a chest CT scan at admittance or during hospitalization, we applied the AI for lung and lung lesion segmentation to obtain lesion volume (LV), and LV/Total Lung Volume (TLV) ratio. ROC analysis was used to extract the best CT criterion in predicting death and ICU admission. Two prognostic models using multivariate logistic regressions were constructed to predict each outcome and were compared using AUC values. The first model ("Clinical") was based on patients' characteristics and clinical symptoms only. The second model ("Clinical+LV/TLV") included also the best CT criterion. Results: LV/TLV ratio demonstrated best performance for both outcomes; AUC of 67.8% (95% CI: 59.5 - 76.1) and 81.1% (95% CI: 75.7 - 86.5) respectively. Regarding death prediction, AUC values were 76.2% (95% CI: 69.9 - 82.6) and 79.9% (95%IC: 74.4 - 85.5) for the "Clinical" and the "Clinical+LV/TLV" models respectively, showing significant performance increase (+ 3.7%; p-value<0.001) when adding LV/TLV ratio. Similarly, for ICU admission prediction, AUC values were 74.9% (IC 95%: 69.2 - 80.6) and 84.8% (IC 95%: 80.4 - 89.2) respectively corresponding to significant performance increase (+ 10%: p-value<0.001). Conclusions: Using a clinical AI software to quantify the COVID-19 lung involvement on chest CT, combined with clinical variables, allows better prediction of death and ICU admission.

How do age and social environment affect the dynamics of death hazard and survival in patients with breast or gynecological cancer in France?

Several studies have investigated the association between net survival (NS) and social inequalities in people with cancer, highlighting a varying influence of deprivation depending on the type of cancer studied. However, few of these studies have accounted for the effect of social inequalities over the follow-up period, and/or according to the age of the patients. Thus, using recent and more relevant statistical models, we investigated the effect of social environment on NS in women with breast or gynecological cancer in France. The data were derived from population-based cancer registries, and women diagnosed with breast or gynecological cancer between 2006 and 2009 were included. We used the European deprivation index (EDI), an aggregated index, to define the social environment of the women included. Multidimensional penalized splines were used to model excess mortality hazard. We observed a significant effect of the EDI on NS in women with breast cancer throughout the follow-up period, and especially at 1.5 years of follow-up in women with cervical cancer. Regarding corpus uteri and ovarian cancer patients, the effect of deprivation on NS was less pronounced. These results highlight the impact of social environment on NS in women with breast or gynecological cancer in France thanks to a relevant statistical approach, and identify the follow-up periods during which the social environment may have a particular influence. These findings could help investigate targeted actions for each cancer type, particularly in the most deprived areas, at the time of diagnosis and during follow-up.

Place of a new radiological index in predicting pulp exposure before intervention for deep carious lesions.

BACKGROUND: During interventions for deep caries lesions without severe symptoms, preserving pulpal vitality is important to ensure treatment success, improve organ prognosis, and decrease cost-effectiveness. Current pre-operative radiographs allow visual estimation but not accurate measurement of lesion depth. PURPOSE: Investigate the ability of ratio 'remaining/total dentin thickness' (RDT/TDT, as determined on pre-operative radiographs) to predict pulp exposure during excavation. METHODS: This retrospective study (January 2018-June 2020) analyzed data on 360 patients. Four independent raters examined standard pre-operative radiographs and their contrasted versions. Lines put at the dentino-enamel junction, the floor of the carious lesion, and the pulp chamber wall allowed deriving RDT/TDT. Inter-rater agreements and concordance were assessed. A logistic regression accounting for measurement errors provided odds ratios that estimated the ability of the RDT/TDT to predict pulp exposure. RESULTS: The median RDT/TDT ratio ranges were 16.8-26.5% on standard and 16.2-24.6% on contrasted radiographs. Inter-rater agreements on RDT/TDT were rather poor and inter-rater reliability was low and similar in standard and contrasted radiographs: the concordance correlation coefficients (95% CIs) were estimated at 0.46 (0.40; 0.51) and 0.46 (0.40; 0.52), respectively. The risk of pulp exposure increased by 2.5 times [odds ratio (95% CI) 2.57 (2.06; 3.20)] per 10-point decrease of the ratio on standard radiographs vs. 4.15 (3.15; 5.46) on contrasted radiographs. CONCLUSION: RDT/TDT ratio is potentially helpful in predicting pulp exposure. However, the measurement errors on RDT and TDT being non-negligible and the interrater agreements poor, there is still place for advances through development of an automated process that will improve reliability and reproducibility of pulp exposure risk assessment. CLINICAL TRIAL: Trial registration number. ClinicalTrials.gov NCT04607395, October 29, 2020.

Relationship between adverse drug reactions and unlicensed/off-label drug use in hospitalized children (EREMI): A study protocol.

INTRODUCTION: To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. METHODS: In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients' electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. STRENGTH AND LIMITATIONS OF THIS STUDY: For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

INTRODUCTION: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. METHODS: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. RESULTS: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m2/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine. CONCLUSION: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.

Multidimensional penalized splines for incidence and mortality-trend analyses and validation of national cancer-incidence estimates.

BACKGROUND: Cancer-incidence and mortality-trend analyses require appropriate statistical modelling. In countries without a nationwide cancer registry, an additional issue is estimating national incidence from local-registry data. The objectives of this study were to (i) promote the use of multidimensional penalized splines (MPS) for trend analyses; (ii) estimate the national cancer-incidence trends, using MPS, from only local-registry data; and (iii) propose a validation process of these estimates. METHODS: We used an MPS model of age and year for trend analyses in France over 1990-2015 with a projection up to 2018. Validation was performed for 22 cancer sites and relied essentially on comparison with reference estimates that used the incidence/health-care ratio over the period 2011-2015. Alternative estimates that used the incidence/mortality ratio were also used to validate the trends. RESULTS: In the validation assessment, the relative differences of the incidence estimates (2011-2015) with the reference estimates were <5% except for testis cancer in men and < 7% except for larynx cancer in women. Trends could be correctly derived since 1990 despite incomplete histories in some registries. The proposed method was applied to estimate the incidence and mortality trends of female lung cancer and prostate cancer in France. CONCLUSIONS: The validation process confirmed the validity of the national French estimates; it may be applied in other countries to help in choosing the most appropriate national estimation method according to country-specific contexts. MPS form a powerful statistical tool for trend analyses; they allow trends to vary smoothly with age and are suitable for modelling simple as well as complex trends thanks to penalization. Detailed trend analyses of lung and prostate cancers illustrated the suitability of MPS and the epidemiological interest of such analyses.

Collaboration between academics, small pharmaceutical company and patient organizations in the development of a new formulation of cysteamine in nephropathic cystinosis: A successful story.

Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required. In this article, we provide an overview of a successful collaboration in nephropathic cystinosis (NC), focusing on what was the key of success, the interactions between academics, the pharmaceutical company and patients organizations. NC is considered as a very rare disease. In 2010, a new formulation of cysteamine, the only available treatment to improve renal outcome of the disease, was proposed by a small American company. Studies were implemented in France under the coordination of an expert of the disease and the clinical investigation center of Lyon. The collaboration resulted in a good recruitment and retention of the patients in the study and most of all in the availability of the new formulation in France. Patients could have facilitated the research by being involved in the early stages of the studies. Involving patients and public early in the process is particularly important in rare diseases as the patient is a great source of knowledge and has his own expectations. Priorities of research, design, conduct and reporting of clinical trials can be defined in collaboration with adults but also with young patients or public, the first concerned in rare diseases. This concept is still to be developed and improved especially with paediatric patients.

Neuropsychological and neuroanatomical phenotype in 17 patients with cystinosis.

BACKGROUND: Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis. METHODS: 17 patients (mean age = 17.6 years, [5.4-33.3]) with cystinosis were included in the study. Neuropsychological assessment was performed including intelligence (Intelligence Quotient (IQ) with Wechsler's scale), memory (Children Memory Scale and Wechsler Memory Scale), visuo-spatial (Rey's figure test) and visuo-perceptual skills assessments. Structural brain MRI (3 T) was also performed in 16 out of 17 patients, with high resolution 3D T1-weighted, 3D FLAIR and spectroscopy sequences. RESULTS: Intellectual efficiency was normal in patients with cystinosis (mean Total IQ = 93). However the Perceptual Reasoning Index (mean = 87, [63-109]) was significantly lower than the Verbal Comprehension Index (mean = 100, [59-138], p = 0.003). Memory assessment showed no difference between visual and verbal memory. But the working memory was significantly impaired in comparison with the general memory skills (p = 0.003). Visuospatial skills assessment revealed copy and reproduction scores below the 50th percentile rank in more than 70% of the patients. Brain MRI showed cortical and sub-cortical cerebral atrophy, especially in the parieto-occipital region and FLAIR hypersignals in parietal, occipital and brain stem/cerebellum. Patients with atrophic brain had lower Total IQ scores compared to non-atrophic cystinosis patients. CONCLUSIONS: Patients with cystinosis have a specific neuropsychological and neuroanatomical profile. We suggest performing a systematic neuropsychological assessment in such children aiming at considering adequate management.

Endoscopic mucosal resection with anchoring of the snare tip: multicenter retrospective evaluation of effectiveness and safety.

Background Endoscopic mucosal resection (EMR) with snare is the recommended technique to resect non-invasive colorectal neoplastic lesions between 10 and 30 mm in diameter. The objective of EMR is to resect completely the neoplastic tissue en bloc and preferably with free margins (R0), avoiding recurrences. Anchoring the tip of the snare in the submucosa is a technical trick that allows snare sliding to be reduced and larger pieces to be caught. The aim of the present study was to evaluate the effectiveness and safety of anchoring-EMR (A-EMR). Methods This was a retrospective analysis of A-EMR procedures for lesions of diameter between 10 and 30 mm (endoscopic evaluation) performed consecutively in four French centers between May 2017 and January 2018. A-EMR was routinely performed for all EMR using Olympus conventional snares (10 or 25 mm). The primary outcome was evaluation of the proportion of R0 resections. Results A total of 141 A-EMR procedures were performed by 10 operators. Mean lesion size was 19.8 mm. Anchoring was feasible in 96.5 % of cases. There were 81.6 % en bloc resections and 70.2 % R0 resections, with the percentage of procedures decreasing with increasing lesion size (82.8 % < 20 mm, 55.3 % 21 - 30 mm, and 50.0 % > 30 mm, P  = 0.002). Complete perforations closed endoscopically occurred in 3/141 cases (2.1 %); none occurred in lesions < 20 mm in size (0 /87). Conclusion The A-EMR technique appears to be promising with a high proportion of R0 for lesions of 10 - 20 mm in size without any perforations. It could also offer an alternative to endoscopic submucosal dissection (ESD), or to hybrid techniques to reach R0 for lesions between 20 and 30 mm in size.

Flexible and structured survival model for a simultaneous estimation of non-linear and non-proportional effects and complex interactions between continuous variables: Performance of this multidimensional penalized spline approach in net survival trend analysis.

Cancer survival trend analyses are essential to describe accurately the way medical practices impact patients' survival according to the year of diagnosis. To this end, survival models should be able to account simultaneously for non-linear and non-proportional effects and for complex interactions between continuous variables. However, in the statistical literature, there is no consensus yet on how to build such models that should be flexible but still provide smooth estimates of survival. In this article, we tackle this challenge by smoothing the complex hypersurface (time since diagnosis, age at diagnosis, year of diagnosis, and mortality hazard) using a multidimensional penalized spline built from the tensor product of the marginal bases of time, age, and year. Considering this penalized survival model as a Poisson model, we assess the performance of this approach in estimating the net survival with a comprehensive simulation study that reflects simple and complex realistic survival trends. The bias was generally small and the root mean squared error was good and often similar to that of the true model that generated the data. This parametric approach offers many advantages and interesting prospects (such as forecasting) that make it an attractive and efficient tool for survival trend analyses.

Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study.

INTRODUCTION: Neoadjuvant chemotherapy has become the treatment of choice for locally advanced breast cancer. Zoledronic acid (ZA) is a bisphosphonate initially used in the treatment of bone metastases because of its antibone resorption effect. Antitumor effects of ZA, including the inhibition of cell adhesion to mineralized bone or the antiangiogenic effect, have been demonstrated. However, the clinical significance of these effects remains to be determined. MATERIALS AND METHODS: We undertook a multicenter open-label randomized trial to analyze the value of adding ZA to neoadjuvant chemotherapy for TNM clinical stage T2/T3 breast cancer. The primary endpoint was the evolution of serum VEGF. RESULTS: The data from 24 patients were included in the ZA group and 26 in the control group. The evolution of serum VEGF was slightly in favor of ZA at 5.5 months (-0.7% vs. +7.5%), without reaching statistical significance (P = .52). The secondary endpoints were the breast conservation rate (higher with ZA; 83.3% vs. 65.4%; P = NS), pathologic complete response (no effect), and circulating tumor cells (odds ratio, 0.68 in favor of ZA; 95% confidence interval, 0.02-24.36). No cases of jaw necrosis or severe renal failure were observed in either group. CONCLUSION: ZA is an antitumor drug of interest because of its multiple effects on tumor biology. Larger trials with longer follow-up that include additional endpoints such as relapse and survival rates would be of interest.

Describing the association between socioeconomic inequalities and cancer survival: methodological guidelines and illustration with population-based data.

BACKGROUND: Describing the relationship between socioeconomic inequalities and cancer survival is important but methodologically challenging. We propose guidelines for addressing these challenges and illustrate their implementation on French population-based data. METHODS: We analyzed 17 cancers. Socioeconomic deprivation was measured by an ecological measure, the European Deprivation Index (EDI). The Excess Mortality Hazard (EMH), ie, the mortality hazard among cancer patients after accounting for other causes of death, was modeled using a flexible parametric model, allowing for nonlinear and/or time-dependent association between the EDI and the EMH. The model included a cluster-specific random effect to deal with the hierarchical structure of the data. RESULTS: We reported the conventional age-standardized net survival (ASNS) and described the changes of the EMH over the time since diagnosis at different levels of deprivation. We illustrated nonlinear and/or time-dependent associations between the EDI and the EMH by plotting the excess hazard ratio according to EDI values at different times after diagnosis. The median excess hazard ratio quantified the general contextual effect. Lip-oral cavity-pharynx cancer in men showed the widest deprivation gap, with 5-year ASNS at 41% and 29% for deprivation quintiles 1 and 5, respectively, and we found a nonlinear association between the EDI and the EMH. The EDI accounted for a substantial part of the general contextual effect on the EMH. The association between the EDI and the EMH was time dependent in stomach and pancreas cancers in men and in cervix cancer. CONCLUSION: The methodological guidelines proved efficient in describing the way socioeconomic inequalities influence cancer survival. Their use would allow comparisons between different health care systems.

An extension of generalized pairwise comparisons for prioritized outcomes in the presence of censoring.

Generalized pairwise comparisons have been proposed to permit a comprehensive assessment of several prioritized outcomes between two groups of observations. This procedure estimates Δ, the net chance of a better outcome with treatment than with control by comparing the patients outcomes among all possible pairs taking one patient from the treatment group and one patient from the control group. For time to event outcomes, the standard procedure of generalized pairwise comparisons is analogous to the Gehan's modification of the Mann-Whitney test which is biased in presence of censored observation and less powerful than Efron's modification of this test. We adapt Efron's modification to generalized pairwise comparisons. We show how a pairwise contribution to Δ can be calculated from the estimates of the survival function in the presence of right-censored data. We performed a simulation study to assess the bias, the type I error and the power of the new procedure. The estimate of Δ with the new procedure is only slightly biased even in presence of heavy censoring. We also show how this bias can be corrected when only one time-to-event outcome is analyzed. The new procedure has higher power in most cases compared to the standard procedure.

Diagnostic value and relative weight of sequence-specific magnetic resonance features in characterizing clinically significant prostate cancers.

PURPOSE: To assess the diagnostic weight of sequence-specific magnetic resonance features in characterizing clinically significant prostate cancers (csPCa). MATERIALS AND METHODS: We used a prospective database of 262 patients who underwent T2-weighted, diffusion-weighted, and dynamic contrast-enhanced (DCE) imaging before prostatectomy. For each lesion, two independent readers (R1, R2) prospectively defined nine features: shape, volume (V_Max), signal abnormality on each pulse sequence, number of pulse sequences with a marked (S_Max) and non-visible (S_Min) abnormality, likelihood of extracapsular extension (ECE) and PSA density (dPSA). Overall likelihood of malignancy was assessed using a 5-level Likert score. Features were evaluated using the area under the receiver operating characteristic curve (AUC). csPCa was defined as Gleason ≥7 cancer (csPCa-A), Gleason ≥7(4+3) cancer (csPCa-B) or Gleason ≥7 cancer with histological extraprostatic extension (csPCa-C). RESULTS: For csPCa-A, the Signal1 model (S_Max+S_Min) provided the best combination of signal-related variables, for both readers. The performance was improved by adding V_Max, ECE and/or dPSA, but not shape. All models performed better with DCE findings than without. When moving from csPCa-A to csPCa-B and csPCa-C definitions, the added value of V_Max, dPSA and ECE increased as compared to signal-related variables, and the added value of DCE decreased. For R1, the best models were Signal1+ECE+dPSA (AUC = 0,805 [95%CI:0,757-0,866]), Signal1+V_Max+dPSA (AUC = 0.823 [95%CI:0.760-0.893]) and Signal1+ECE+dPSA [AUC = 0.840 (95%CI:0.774-0.907)] for csPCa-A, csPCA-B and csPCA-C respectively. The AUCs of the corresponding Likert scores were 0.844 [95%CI:0.806-0.877, p = 0.11], 0.841 [95%CI:0.799-0.876, p = 0.52]) and 0.849 [95%CI:0.811-0.884, p = 0.49], respectively. For R2, the best models were Signal1+V_Max+dPSA (AUC = 0,790 [95%CI:0,731-0,857]), Signal1+V_Max (AUC = 0.813 [95%CI:0.746-0.882]) and Signal1+ECE+V_Max (AUC = 0.843 [95%CI: 0.781-0.907]) for csPCa-A, csPCA-B and csPCA-C respectively. The AUCs of the corresponding Likert scores were 0. 829 [95%CI:0.791-0.868, p = 0.13], 0.790 [95%CI:0.742-0.841, p = 0.12]) and 0.808 [95%CI:0.764-0.845, p = 0.006]), respectively. CONCLUSION: Combination of simple variables can match the Likert score's results. The optimal combination depends on the definition of csPCa.

Performance of two formal tests based on martingales residuals to check the proportional hazard assumption and the functional form of the prognostic factors in flexible parametric excess hazard models.

Net survival, the one that would be observed if the disease under study was the only cause of death, is an important, useful, and increasingly used indicator in public health, especially in population-based studies. Estimates of net survival and effects of prognostic factor can be obtained by excess hazard regression modeling. Whereas various diagnostic tools were developed for overall survival analysis, few methods are available to check the assumptions of excess hazard models. We propose here two formal tests to check the proportional hazard assumption and the validity of the functional form of the covariate effects in the context of flexible parametric excess hazard modeling. These tests were adapted from martingale residual-based tests for parametric modeling of overall survival to allow adding to the model a necessary element for net survival analysis: the population mortality hazard. We studied the size and the power of these tests through an extensive simulation study based on complex but realistic data. The new tests showed sizes close to the nominal values and satisfactory powers. The power of the proportionality test was similar or greater than that of other tests already available in the field of net survival. We illustrate the use of these tests with real data from French cancer registries.

Trends in net survival from 15 cancers in six European Latin countries: the SUDCAN population-based study material.

The aim of the SUDCAN collaborative study was to compare the net survival from 15 cancers diagnosed in 2000-2004 in six European Latin countries and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis from 1992 to 2004 in France, Italy, Spain, and Switzerland, and from 2000 to 2004 in Belgium and Portugal. This paper presents a detailed description of the data analyzed and quality indicators. Incident cases from Belgium, France, Italy, Portugal, Spain, and Switzerland were retrieved from 56 general or specialized population-based cancer registries that participated in the EUROCARE-5 database. Fifteen cancer sites were analyzed. The data were checked according to the EUROCARE protocol. The percentages of excluded cases, cases based on death-certificate only, cases lost to follow-up at 5 years after diagnosis, and the proportions of microscopically verified cases were evaluated across countries and cancer sites. Data exclusions for major flaws were negligible. Cases based on death-certificate only were quite rare, except for some poor-prognosis cancers in some countries. The site-specific proportions of microscopically verified cases were generally high, but slightly lower in Italy than elsewhere. The percentage of cases lost to follow-up at 5 years after diagnosis was generally low. The net survival analyses in 2000-2004 included 873 314 tumors, whereas trend analyses included 1 426 004 tumors. The quality of the data analyzed was generally good. In fact, the analyzed data have been already checked and accepted for EUROCARE-5. However, slight differences in quality indexes, for some cancers, should be kept in mind in the interpretation of survival comparisons across countries.

New insights into survival trend analyses in cancer population-based studies: the SUDCAN methodology.

The main objective of the SUDCAN study was to compare, for 15 cancer sites, the trends in net survival and excess mortality rates from cancer 5 years after diagnosis between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. The study period ranged from 6 (Portugal, 2000-2005) to 18 years (Switzerland, 1989-2007). Trend analyses were carried out separately for each country and cancer site; the number of cases ranged from 1500 to 104 000 cases. We developed an original flexible excess rate modelling strategy that accounts for the continuous effects of age, year of diagnosis, time since diagnosis and their interactions. Nineteen models were constructed; they differed in the modelling of the effect of the year of diagnosis in terms of linearity, proportionality and interaction with age. The final model was chosen according to the Akaike Information Criterion. The fit was assessed graphically by comparing model estimates versus nonparametric (Pohar-Perme) net survival estimates. Out of the 90 analyses carried out, the effect of the year of diagnosis on the excess mortality rate depended on age in 61 and was nonproportional in 64; it was nonlinear in 27 out of the 75 analyses where this effect was considered. The model fit was overall satisfactory. We analysed successfully 15 cancer sites in six countries. The refined methodology proved necessary for detailed trend analyses. It is hoped that three-dimensional parametric modelling will be used more widely in net survival trend studies as it has major advantages over stratified analyses.