In paediatric acute lymphoblastic leukaemia (ALL), focus has shifted towards preventing treatment-related complications, including venous thromboembolism, the cause of significant mortality and ...morbidity. To better understand thrombogenic mechanisms during induction treatment, we studied the number, origin and procoagulant activity of extracellular vesicles (EVs) and P-selectin level throughout the induction course in 24 paediatric patients. EVs were mainly of platelet origin. We observed a significant increase in EV number, in platelet EV number and P-selectin level throughout the induction course. There was a correlation between higher EV and platelet EV number, P-selectin level, higher platelet count and leucocyte count. We also observed a correlation between higher EV procoagulant activity and higher platelet count and leucocyte count and higher P-selectin level. Older age and T phenotype were associated with a higher EV procoagulant activity. Platelet EV generation may play a role in thrombogenic complications in ALL patients and could serve as a biomarker to identify patients with a high risk of thrombosis. As a marker of platelet activation, P-selectin may be another relevant marker with the advantage of being easier to analyse in clinical practice.
Childhood cancer survivors (CCS) may require lifelong medical care due to late effects of cancer treatments. Little is known about of their healthcare utilization and expenditures at long-term ...especially in publicly funded health care system. We aim to estimate and describe the health care expenditures among long-term CCS in France.
A total of 5319 five-year solid CCS diagnosed before the age of 21 between 1945 and 2000 in France were identified in the French Childhood Cancer Survivors Study cohort (FCCSS) and the French cancer registry. Information about health care expenditure was taken from the French national health data system between 2011 and 2016, and was described according to survivors' characteristics. Generalized linear models were used to determine associations between health care expenditures and survivors' characteristics.
Mean annual amount of healthcare expenditures was € 4,255. Expenditures on hospitalizations and pharmacy represents 60% of total expenditures. Mean annual of healthcare expenditures were higher at increasing age, among women survivors (€ 4,795 vs € 3,814 in men) and in central nervous system (CNS) tumor survivors (€ 7,116 vs € 3,366 in lymphoma and € 3,363 in other solid tumor survivors).
Childhood cancer survivorship is associated with a substantial economic burden in France. We found that female gender and CNS primary cancer were associated with increased healthcare expenditures.
The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer ...survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006-2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval CI 2.46-2.52) and the RBDR was 3.49 (95% CI 3.46-3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio RR 1.62, 95% CI 1.53-1.70), radiotherapy (RR 2.11, 95% CI 1.99-2.24) or both (RR 2.59, 95% CI 2.46-2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS.
Thromboembolic events are frequent and serious complications of acute lymphoblastic leukaemia treatment. The importance of chemotherapy in the pathogenesis of this increased risk is enhanced by the ...fact that thrombosis rarely occurs at diagnosis. Our study aims at investigating the effect of chemotherapy on pro-coagulant activity (PCA), phosphatidylserine (PS) exposure, tissue factor (TF) activity and derived extracellular vesicles (EV) of Jurkat cells. Jurkat cells were treated with two commonly used chemotherapeutics: Vincristine (VCR) or Daunorubicin (DNR), at relevant concentrations. PCA of cells and derived EV were evaluated using Thrombin generation Assay (TGA). Cells or EV were incubated with annexin V or anti TF antibodies to assess the respective contribution of TF and PS. PS exposure on cells was analysed by flow cytometry. Derived EV were evaluated in fluorescence microscopy and flow cytometry. Untreated Jurkat cells and EV support thrombin generation. Thrombin generation was abolished when PS activity was inhibited by annexin V. VCR treatment resulted in a time dependent increase of thrombin generation. After VCR exposure, TF activity increased as well as PS exposure increased on the cell surface. The increase in TF activity was abolished by annexin V indicating that PS was required. A spontaneous release of EV from Jurkat cells was observed and VCR treatment increased the number of generated EV. Our results indicate that VCR increased the PCA of Jurkat cells predominantly through PS exposure and increased EV generation. Lymphoid blasts derived EV could be biomarkers to determine high thrombotic risk ALL patients.
Background
Cancer treatments of the last decades improve the survival rate of children and adolescents. However, chemo- and radiotherapy result in gonadal damage, leading to acute ovarian failure and ...sterility. The preservation of fertility is now an integral part of care of children requiring gonadotoxic treatments. Ovarian tissue cryopreservation (OTC) is an effective fertility preservation option that allows long-term storage of primordial follicles, subsequent transplantation, and restoration of endocrine function and fertility. The efficacy of this technique is well-demonstrated in adults but the data are scarce for pediatric patients. Currently, OTC represents the only possibility of preserving the potential fertility in prepubertal girls.
Procedure
This is a retrospective study of OTC practice of two French centers from January 2004 to May 2020. A total of 72 patients from pediatric units underwent cryopreservation of ovarian tissue before gonadotoxic therapy for malignant or non-malignant diseases. The ovarian cortex was cut into fragments and the number of follicles per square millimeter was evaluated histologically. The long-term follow-up includes survival rate and hormonal and fertility status.
Results
The mean age of patients at OTC was 9.3 years 0.2–17 and 29.2% were postpubertal; 51 had malignant diseases and 21 had non-malignant diseases. The most frequent diagnoses included acute leukemia, hemoglobinopathies, and neuroblastoma. Indication for OTC was stem cell transplantation for 81.9% (
n
= 59) of the patients. A third of each ovary was collected for 62.5% (
n
= 45) of the patients, a whole ovary for 33.3% (
n
= 24) of the patients, and a third of one ovary for 4.2% (
n
= 3) of the patients. An average of 17 fragments 5–35 per patient was cryoconserved. A correlation was found between the age of the patients and the number of fragments (
p
< 0.001). More fragments were obtained from partial bilateral harvesting than from whole ovary harvesting (
p
< 0.05). Histological analysis of ovarian tissue showed a median of 6.0 primordial follicles/mm
2
0.0–106.5 and no malignant cells were identified. A negative correlation was found between age and follicular density (
p
< 0.001). Median post-harvest follow-up was 92 months 1–188. A total of 15 girls had died, 11 were still under treatment for their pathology, and 46 were in complete remission. Of all patients, 29 (40.2%) were subjected to a hormonal status evaluation and 26 were diagnosed with premature ovarian insufficiency (POI) (
p
< 0.001). One patient had undergone thawed ovarian tissue transplantation.
Conclusion
OTC should be proposed to all girls with high risk of developing POI following gonadotoxic therapies in order to give them the possibility of fertility and endocrine restoration.
The aim of this study was to examine whether texture analysis features on pretreatment contrast-enhanced CT images could predict adequate response (AR) or inadequate response (IR) after two cycles of ...chemotherapy in pediatric Hodgkin's lymphoma (PHL).
This retrospective single-center study included 32 children and adolescents with HL. Texture analysis was independently performed by two radiologists using pretreatment CT scans. The mean gray level, standard deviation, entropy, kurtosis, and skewness were derived from pixel distribution histograms before and after spatial filtration ranging from two (fine texture) to six (coarse texture). Interobserver reliability was studied using interobserver correlation coefficients (ICCs) to select texture parameters. Relationships between early response assessment (ERA) to induction therapy and associated factors were studied using Student's
-tests and a lasso penalized logistic regression analysis.
Of the 32 patients, IR was observed in 13 and AR in 19. Inter-reader agreement was good to excellent (ICC > 0.75) for all parameters except skewness and kurtosis without filtration and at spatial scale filtration (SSF) = 2. These parameters were excluded from the analysis. The
-test identified only entropy at SSF = 2 (
value = 0.039) as a potential predictor of ERA. No parameters were significantly associated with ERA, according to a lasso penalized logistic regression.
No textural parameters were identified as predictors of ERA after two cycles of chemotherapy in PHL.
due to increasing survival rates in childhood acute lymphoblastic leukemia (ALL), the number of survivors has been expanding. A significant proportion of these survivors can experience long-term ...emotional and psychosocial problems. However, the exact risk factors remain inconclusive. We investigated potential risk factors for decreased daily life quality and life challenges in long-term childhood ALL survivors enrolled between 1971 and 1998 in EORTC studies.
self-report questionnaires were collected from 186 survivors (109 females; mean age at diagnosis 5.62 years, range 0.2-14.7; median time since diagnosis of 20.5 years (12.9-41.6)), including the Short-Form Health Survey (SF-12) and Impact of Cancer-Childhood Survivors (IOC-CS). Multivariable linear regression models were used to assess the impact of gender, age at diagnosis, relapse/second neoplasm, National Cancer Institute (NCI) risk group and cranial radiotherapy on 2 subscales of the SF-12 (physical and mental health) and five subscales of the IOC-CS (life challenges, body and health, personal growth, thinking and memory problems and socializing).
mental component scores of SF-12 were not significantly associated with any risk factor. Physical component scores were lower in relapsed, irradiated and NCI high-risk patients. Regarding IOC-CS negative impact subscales, life challenges was more negatively impacted by cancer in female, younger (i.e., <6 years) and relapsed patients. Regarding the positive impact scales, personal growth was more positively impacted in relapsed patients, whereas body and health, and socializing, were less positively impacted in these patients, compared to non-relapsed patients. Socializing was more positively impacted in older patients (>6 years).
this study demonstrates that long-term outcomes can be both adverse and positive, depending on the patient's demographic and clinical characteristics. Younger, female, and relapsed patients might encounter more life challenges years after their disease, while physical challenges could occur more often in relapsed and high-risk patients. Finally, the positive effect on socializing in the older patients sheds new light on the importance of peer interactions for this subgroup. Specific individual challenges thus need specialized support for specific subgroups.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to ...chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15–22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971–1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10–17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).
Acute lymphoblastic leukaemia (ALL) is the most common type of cancer diagnosed in children. Improvement in the treatment has resulted in survival rates of nearly 85% with modern intensive ...chemotherapy. However, intensive treatment imposes morbidity and mortality. Thromboembolic events are among the more frequent and serious complications of acute lymphoblastic leukaemia. They represent a potentially reversible cause of morbidity and mortality. In the largest study, the rate of thrombosis was 5.2% and half of thrombotic events occurs in the central nervous system. The pathogenesis of this increased thrombotic risk is not fully understood, but probably includes a combination of variables related to the disease itself, its treatment, and the host. In literature, there are few studies about the role of lymphoid blasts and of derived microparticules (MP) in these complications.
JURKAT ALL cell line was exposed to Vincristine (VCR) or Doxorubicin (DOX) at the therapeutic concentrations of respectively 300ng/ml and 20ng/ml during 4 or 24 hours (h). Cells viability was studied with MTT tetrazolium reduction assay. Tissue factor (TF) expression was studied by RT PCR and Western Blot. Thrombin generation was estimated by Thrombin generation assay (TGA). Antibody (Ab) against TF and Annexin V (AV) were used to assess respectively the role of TF and of phosphatidylserine. MP derived from JURKATT cells were isolated by two centrifugations (15 minutes at 1500x g and 45 minutes at 15000x g). MP were observed and quantified by fluorescence microscopy after a labelling with AV Alexa. TGA was used to evaluate MP thrombin generation.
After 4h and 24h of incubation with VCR, cells viability was respectively of 109% and 42%. JURKAT cell line expressed TF mRNA and protein. This expression did not vary with chemotherapy. JURKAT cell line was able to support thrombin generation. After a treatment during 24h with VCR, thrombin generation was significantly higher with a significant modification of all parameters of TGA. AV induced a complete inhibition of thrombin generation whereas TF Ab induced a delay in the initiation of thrombin generation. This delay was significantly higher after 24h incubation with VCR (182%) than after 4h (114%). At baseline, JURKAT cell line released MP which were observed and quantified by florescence microscopy. MP induced thrombin generation. After 4 and 24h of incubation with VCR, the number of MP increased significantly (respectively 74% and 142%). The size of MP was significantly smaller after an incubation of 24h. 24h exposure to VCR significantly increased MP thrombin generation. AV induced a complete inhibition of thrombin generation. TF Ab induced a delay in the initiation of thrombin generation. Despite its effect on cells viability (115% after 4h and 38% after 24h), DOX treatment during 4h or 24h did not induce statistically significant variations in thrombin generation by JURKAT cells or by derived MP.
The role of blasts in thromboembolic events has been mostly studied in acute myeloid leukaemia but only rarely in ALL. The role of high levels of MP has been studied in various diseases complicated by thrombosis but not in ALL. According to the results of this study, lymphoid blasts could play a role in thrombosis events at the initiation of treatment in ALL. When exposed to VCR, JURKAT cell line is able to support thrombin generation with a time-dependant effect of VCR. Pro-coagulant phospholipids exposure on blasts and derived MP plays a major role in thrombin generation.TF has a role in the initiation of coagulation. Inhibition of TF effect by Ab is also time-dependant, suggesting that despite the absence of modification in TF expression, VCR may induce modifications in TF activity, maybe by a mechanism of decryption via interactions with phosphatidylserine. Our data also suggest that MP could be potential markers and targets in the prevention of thrombosis in ALL patients.
No relevant conflicts of interest to declare.
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