Survival improvement over time of 960 s-AML patients included in 13 EORTC-GIMEMA-HOVON trials

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p 60 years of age (n = 502), the OS was dismal, and there was no improvement over time

Data from: Mammal-induced trophic cascades in invertebrate food webs are modulated by grazing intensity in subalpine grassland

1. Even though mammalian herbivores can exert strong indirect effects on other animals by altering the vegetation, the study of trophic cascades retains a focus on apex predators and their top-down forces. Bottom-up trophic interaction chains induced by mammalian herbivores, particularly in invertebrate food webs, remain largely unexplored. 2. We tested whether effects of mammalian herbivores on the vegetation ricochet back up several trophic levels of the invertebrate food web. We further tested two alternative hypotheses: the strength of herbivore-induced indirect interactions either increases with plant productivity because of a concurrent higher grazing intensity, or it decreases because of a higher plant tolerance to grazing. 3. We progressively excluded large, medium, and small herbivorous mammals from replicated plots of 6 m2 in productive, intensively grazed short-grass vegetation and less productive, less intensively grazed tall-grass vegetation of subalpine grasslands. We measured vegetation quantity, quality, structure, and composition, and determined the abundance of invertebrate herbivores, detritivores, omnivores, and predators. We used Structural Equation Modelling to test vegetation-mediated cascading effects of the different mammalian herbivores across different trophic groups of invertebrates. 4. In the short-grass vegetation, mammals caused changes in vegetation quantity and thickness. These changes directly affected detritivorous and predatory invertebrate abundance, yet indirectly affected predatory and omnivorous invertebrates through a bottom-up trophic cascade via changes in herbivorous invertebrate abundance. In the tall-grass vegetation, mammal-induced changes in vegetation quality and composition affected detritivorous invertebrates and in turn omnivorous invertebrates, but these cascading effects were weaker than those in the short-grass vegetation. Smaller mammals were at least as important as large mammals in structuring the invertebrate food web. 5. Our results demonstrate that differently sized mammalian herbivores can trigger trophic cascades in the local invertebrate food web. Our findings further support the hypothesis that herbivore-induced indirect interactions are stronger in more productive systems because of higher foraging intensity, as opposed to the hypothesis that a higher grazing tolerance of plants should dampen herbivore-induced indirect interactions in productive systems

Data from: Mammal-induced trophic cascades in invertebrate food webs are modulated by grazing intensity in subalpine grassland

1. Even though mammalian herbivores can exert strong indirect effects on other animals by altering the vegetation, the study of trophic cascades retains a focus on apex predators and their top-down forces. Bottom-up trophic interaction chains induced by mammalian herbivores, particularly in invertebrate food webs, remain largely unexplored. 2. We tested whether effects of mammalian herbivores on the vegetation ricochet back up several trophic levels of the invertebrate food web. We further tested two alternative hypotheses: the strength of herbivore-induced indirect interactions either increases with plant productivity because of a concurrent higher grazing intensity, or it decreases because of a higher plant tolerance to grazing. 3. We progressively excluded large, medium, and small herbivorous mammals from replicated plots of 6 m2 in productive, intensively grazed short-grass vegetation and less productive, less intensively grazed tall-grass vegetation of subalpine grasslands. We measured vegetation quantity, quality, structure, and composition, and determined the abundance of invertebrate herbivores, detritivores, omnivores, and predators. We used Structural Equation Modelling to test vegetation-mediated cascading effects of the different mammalian herbivores across different trophic groups of invertebrates. 4. In the short-grass vegetation, mammals caused changes in vegetation quantity and thickness. These changes directly affected detritivorous and predatory invertebrate abundance, yet indirectly affected predatory and omnivorous invertebrates through a bottom-up trophic cascade via changes in herbivorous invertebrate abundance. In the tall-grass vegetation, mammal-induced changes in vegetation quality and composition affected detritivorous invertebrates and in turn omnivorous invertebrates, but these cascading effects were weaker than those in the short-grass vegetation. Smaller mammals were at least as important as large mammals in structuring the invertebrate food web. 5. Our results demonstrate that differently sized mammalian herbivores can trigger trophic cascades in the local invertebrate food web. Our findings further support the hypothesis that herbivore-induced indirect interactions are stronger in more productive systems because of higher foraging intensity, as opposed to the hypothesis that a higher grazing tolerance of plants should dampen herbivore-induced indirect interactions in productive systems

Data_JAE-2016-00436.R4

Data_JAE-2016-00436.R

Mammalian herbivores affect leafhoppers associated with specific plant functional types at different timescales

1. Theory predicts that mammalian herbivores affect the quantity and quality of plants on which they preferentially feed in the short term. In the longer term, they can promote either preferred or less preferred plants, depending on whether preferred plants are adapted or sensitive to grazing. Less clear are the short- and long-term responses of herbivorous insects to mammalian herbivory, and how these responses depend on the specific plants or plant functional types on which the insects feed.\ud \ud 2. We progressively excluded large, medium, and small mammals for five growing seasons in two subalpine vegetation types with long-term differences in mammalian grazing intensity. Short-grass vegetation has a history of intensive grazing, while tall-grass vegetation has been grazed less intensively. We tested whether mammals altered the abundance and body size of leafhoppers specialized on specific plant functional types (grasses, sedges, forbs, or legumes/forbs), distinguishing between short-term (exclosures) and long-term (vegetation types) differences in mammalian grazing pressure. Furthermore, we assessed whether leafhoppers’ responses were explained by changes in biomass or quality of the plant functional types on which they feed.\ud \ud 3. In the short term, mammal exclosures increased the abundance of grass- and forb-feeding leafhoppers via increases in the biomass of grasses and forbs, regardless of vegetation type. Both grasses and forbs are preferred food plants of mammals. In the long term, the biomass of sedges, which are less preferred by mammals, increased in the less intensively grazed tall-grass vegetation. This resulted in a higher abundance of sedge-feeding leafhoppers. The small size of these sedge feeders lowered the average leafhopper body size in the tall-grass vegetation. Plant nutritional quality did not explain any effects of exclusions or vegetation types.\ud \ud 4. Our results demonstrate that both short- and long-term effects of mammalian herbivores on the biomass of specific plant functional types caused concurrent changes in the abundance of specialized herbivorous insects, which scaled up to community-wide shifts in insect body size, a key life-history trait. A plant-functional-type approach can thus help to predict how overabundance or extinction of mammalian herbivores impacts on other components of the food web at various timescales

Data from: Mammalian herbivores affect leafhoppers associated with specific plant functional types at different timescales

1. Theory predicts that mammalian herbivores affect the quantity and quality of plants on which they preferentially feed in the short term. In the longer term, they can promote either preferred or less preferred plants, depending on whether preferred plants are adapted or sensitive to grazing. Less clear are the short- and long-term responses of herbivorous insects to mammalian herbivory, and how these responses depend on the specific plants or plant functional types on which the insects feed. 2. We progressively excluded large, medium, and small mammals for five growing seasons in two subalpine vegetation types with long-term differences in mammalian grazing intensity. Short-grass vegetation has a history of intensive grazing, while tall-grass vegetation has been grazed less intensively. We tested whether mammals altered the abundance and body size of leafhoppers specialized on specific plant functional types (grasses, sedges, forbs, or legumes/forbs), distinguishing between short-term (exclosures) and long-term (vegetation types) differences in mammalian grazing pressure. Furthermore, we assessed whether leafhoppers’ responses were explained by changes in biomass or quality of the plant functional types on which they feed. 3. In the short term, mammal exclosures increased the abundance of grass- and forb-feeding leafhoppers via increases in the biomass of grasses and forbs, regardless of vegetation type. Both grasses and forbs are preferred food plants of mammals. In the long term, the biomass of sedges, which are less preferred by mammals, increased in the less intensively grazed tall-grass vegetation. This resulted in a higher abundance of sedge-feeding leafhoppers. The small size of these sedge feeders lowered the average leafhopper body size in the tall-grass vegetation. Plant nutritional quality did not explain any effects of exclusions or vegetation types. 4. Our results demonstrate that both short- and long-term effects of mammalian herbivores on the biomass of specific plant functional types caused concurrent changes in the abundance of specialized herbivorous insects, which scaled up to community-wide shifts in insect body size, a key life-history trait. A plant-functional-type approach can thus help to predict how overabundance or extinction of mammalian herbivores impacts on other components of the food web at various timescales

Comparative analysis of somatic variant calling on matched FF and FFPE WGS samples

BACKGROUND: Research grade Fresh Frozen (FF) DNA material is not yet routinely collected in clinical practice. Many hospitals, however, collect and store Formalin Fixed Paraffin Embedded (FFPE) tumor samples. Consequently, the sample size of whole genome cancer cohort studies could be increased tremendously by including FFPE samples, although the presence of artefacts might obfuscate the variant calling. To assess whether FFPE material can be used for cohort studies, we performed an in-depth comparison of somatic SNVs called on matching FF and FFPE Whole Genome Sequence (WGS) samples extracted from the same tumor. METHODS: Four variant callers (i.e. Strelka2, Mutect2, VarScan2 and Shimmer) were used to call somatic variants on matching FF and FFPE WGS samples from a metastatic prostate tumor. Using the variants identified by these callers, we developed a heuristic to maximize the overlap between the FF and its FFPE counterpart in terms of sensitivity and precision. The proposed variant calling approach was then validated on nine matched primary samples. Finally, we assessed what fraction of the discrepancy could be attributed to intra-tumor heterogeneity (ITH), by comparing the overlap in clonal and subclonal somatic variants. RESULTS: We first compared variants between an FF and an FFPE sample from a metastatic prostate tumor, showing that on average 50% of the calls in the FF are recovered in the FFPE sample, with notable differences between callers. Combining the variants of the different callers using a simple heuristic, increases both the precision and the sensitivity of the variant calling. Validating the heuristic on nine additional matched FF-FFPE samples, resulted in an average F1-score of 0.58 and an outperformance of any of the individual callers. In addition, we could show that part of the discrepancy between the FF and the FFPE samples can be attributed to ITH. CONCLUSION: This study illustrates that when using the correct variant calling strategy, the majority of clonal SNVs can be recovered in an FFPE sample with high precision and sensitivity. These results suggest that somatic variants derived from WGS of FFPE material can be used in cohort studiesUGent Bijzonder onderzoeksfonds, Agentschap voor Innovatie door Wetenschap en Technologie (IWT) [NEMOA] and Fonds Wetenschappelijk Onderzoek.https://bmcmedgenomics.biomedcentral.compm2020Genetic

Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.

peer reviewedSTUDY QUESTION: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors? SUMMARY ANSWER: We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors. WHAT IS KNOWN ALREADY: Survival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies. STUDY DESIGN, SIZE, DURATION: Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046). LIMITATIONS, REASONS FOR CAUTION: The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls. WIDER IMPLICATIONS OF THE FINDINGS: Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors. STUDY FUNDING/COMPETING INTEREST(S): This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared. TRIAL REGISTRATION NUMBER: NCT01298388 (clinicaltrials.gov)

Socio-economic outcomes among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: Results of the 58LAE study.

peer reviewed("[en] OBJECTIVE: The objective of this study is to evaluate the socio-economic outcomes of survivors of childhood acute lymphoblastic leukaemia (ALL). METHODS: Childhood ALL adult survivors, enrolled in EORTC trials between 1971 and 1998 in France and Belgium, were invited to fill out a questionnaire with information about their socio-economic situation (living with a partner, having a university degree, having a job, working part time and history of having a paid job). The outcomes were compared with two matched control populations. RESULTS: Among 1418 eligible patients, 507 (35.8%) participated, including 39 (8%) and 61 (12%) patients who received a haematopoietic stem cell transplantation (HSCT) and a cranial radiotherapy (CRT), respectively. The median time to follow-up was 20 years, and median age was 25 years. Survivors showed a socio-economic level at least as good as controls. HCST and CRT were associated with a higher probability of not obtaining a bachelor degree (respectively OR = 3.49, 95% CI: 1.46-8.35 and OR = 2.31, 95% CI: 1.04-5.15), HSCT was associated with unemployment (OR = 2.89, 95% CI: 1.09-7.65) and having a relapse was associated with a higher probability of not having a partner (OR = 1.88, 95% CI: 1.01-3.51) adjusting for confounders. CONCLUSION: Childhood ALL survivors showed a high level of socio-economic participation. HCST and CRT were associated with poorer functioning.","[en] ",""