Venous thromboembolism (VTE) are rare but potentially life-threatening conditions in children, usually associated with underlying medical conditions. Some children with diagnosed VTE have genetic risk factors for the development of VTE, as well as for recurrent complications. This study reports risk factors for developing VTE in a homogeneous population of children and adolescents. A total of 155 children and adolescents, aged 0-21 years, who were diagnosed with VTE at the University Children's Hospital, UMC Ljubljana, between July 2006 and October 2021, were included. The median age at the time of the VTE diagnosis was 12.0 years (interquartile range: 1-7 years). Associated medical conditions were present in 75.5% of patients, and thrombophilia was diagnosed in 43.2% of patients. Oncological disease accounted for 27.7% of cases, while infections were found to be the most significant acquired risk factor (17.4%), followed by the presence of a central venous catheter (15.5%). Genetic thrombophilia markers were identified in 27.1% of patients, with the highest frequency in adolescents (62.5%). Factor V (FV) Leiden heterozygote was the most common marker (9.6% of patients), followed by elevated factor VIII (FVIII) activity (5.8%) and elevated Lp(a) levels (5.2%). Combined thrombophilia markers were found in 52.2% of patients. In addition to inherited thrombophilia, 83.3% of patients had acquired risk factors. Compared to previously reported prevalence, a lower occurrence of FV Leiden heterozygote, elevated Lp(a) levels, elevated FVIII activity and antiphospholipid syndrome was observed in our population.

BACKGROUND:Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) is assessed by cell counting and cytomorphology from cerebrospinal fluid (CSF) and is used for treatment stratification worldwide. The ratio of "CNS2" patients in clinical trials ranges from 3% to 40%, with unclear prognostic significance. PROCEDURE:To assess real-world practice, a survey was distributed globally. Questions focused on the systemic treatment allowed before the staging lumbar puncture, sample handling, methodological details of different analytics, and staging definitions. RESULTS:Eighty-two centers from 47 countries from 5 continents responded. Contraindications and timing of sampling and applied CSF test modalities are heterogeneous. CSF volumes used for cytospins and flow cytometry range widely (15-3000 and 200-4000 µL, respectively). Test positivity definitions vary between ≥1 and ≥5 identified blasts for cytospin and ≥1 to ≥50 blasts for flow cytometry. Differences in practice were seen between countries in the same ALL consortium and within individual countries. CONCLUSIONS:The observed heterogeneity impacts CNS staging and treatment decisions worldwide. Our results may explain the conflicting published evidence on the prognostic value of minimal leukemic CNS involvement. A global consensus on CNS diagnostics and a more detailed reporting of CNS staging methods in clinical studies are urgently needed.

BACKGROUND:The Acute Lymphoblastic Leukemia InterContinental (ALL-IC) Study Group exemplifies the potential of broad international collaboration. Patient outcomes have improved by standardizing therapeutic options and employing flow cytometry-based minimal residual disease (MRD) for treatment stratification. Nevertheless, relapse occurs in 10%-20% of cases, with survival rates falling short of benchmarks set by top-tier published studies. OBJECTIVES:We aimed to unify treatment guidelines for children with first relapse of ALL across the ALL-IC network, analyze post-relapse outcomes, and report findings from an observational registry. METHODS:Patients were stratified as standard-risk (SR) or high-risk (HR) based on relapse features and genetics. HR criteria included T-cell immunophenotype, very early or early isolated bone marrow relapse, and relapse post-stem cell transplant (SCT). SR was assigned to all others. SCT was indicated in the whole HR group and in SR patients with poor responses (MRD ≥ 0.1% on Day 29). RESULTS:Among 370 patients (mean age 9 years; 33.2% female) diagnosed with first relapse between 2017 and 2021, 90.5% had received ALL-IC-Berlin-Frankfurt-Münster (BFM) 2009 treatment initially. Upon relapse, 46.8% were classified as SR and 53.2% as HR. Complete remission rates post-induction were 84% (SR) and 56% (HR). MRD < 0.1% was achieved by 53% (SR) and 29% (HR). Five-year overall survival was 50.5% (74% SR, 32% HR). HR outcomes were hindered by disease progression, treatment toxicity, and posttransplant complications. CONCLUSIONS:This inaugural ALL-IC REL Consortium report demonstrates promising SR outcomes, akin to the International Study for the Treatment of Childhood Relapsed ALL (IntReALL) findings, but highlights poor HR outcomes with standard chemotherapy. Novel therapeutic strategies are urgently needed in upcoming ALL-IC-BFM REL protocols.

Acute lymphoblastic leukemia (ALL) is among the most curable pediatric cancers, yet relapse involving the central nervous system (CNS) remains a major therapeutic obstacle. In this prospective cohort, 97 children (aged 1.1-18.2 years) experiencing their first CNS relapse were enrolled in the ALL-IC REL study. Relapses were classified as isolated CNS (i-CNS, n = 43) or combined CNS (c-CNS, n = 54), and patients received treatment through standard- or high-risk regimens, encompassing chemotherapy, cranial irradiation, and allogeneic stem cell transplantation. The estimated 2-year event-free survival was 40.0%, and overall survival 49.4%, closely matching outcomes reported internationally. Survival rates were comparable across i-CNS and c-CNS relapses, while induction failure occurred more frequently in c-CNS. Multivariable analysis identified female sex, T-cell phenotype, and very early relapse as independent predictors of poor prognosis. These results underscore the critical necessity for risk-adapted therapy techniques and the incorporation of innovative medicines into forthcoming procedures.

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients’ lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.

Uvod: Uspešna implementacija koncepta družini usmerjene zdravstvene oskrbe v klinično okolje je velik izziv za multidisciplinarni tim pri zdravljenju otrok z rakom in njihovih družin. Namen raziskave je bil preučiti percepcijo in prakso tima v slovenskem okolju. Metode: Raziskava je bila izvedena z anketnim vprašalnikom o oskrbi, osredotočeni na družino v pediatrični onkologiji (angl. Family-Centered Care Questionnaire-Revised). Vzorec je vključeval 80 članov multidisciplinarnega tima, od katerih je 63 vrnilo izpolnjene anketne vprašalnike. Podatki so bili analizirani s programom SPSS, uporabljeni so bili deskriptivni in interferenčni statistični postopki, vključno z Mann-Whitneyjevim U-testom in Kruskal-Wallisovim testom. Rezultati: Raziskava je pokazala, da se multidisciplinarni tim, ki obravnava otroke z rakom, v veliki meri zaveda pomena oskrbe, osredinjene na otroka in družino (x = 2,28, s = 0,550). Obstajajo odstopanja v zavedanju pomena skrbi za celotno družino (x = 2,60, s = 0,670). Razlike so bile ugotovljene glede vključevanja staršev v oskrbo, predvsem med strokovnjaki z različnimi delovnimi izkušnjami (p = 0,024) ter med negovalnimi timi intenzivne terapije in onkologije (p < 0,001). Diskusija in zaključek: Moramo si prizadevati za kakovostno sodobno zdravstveno oskrbo, ki zadostuje potrebam otroka in staršem ter vodi do boljših rezultatov zdravljenja, krajših hospitalizacij, večjega zadovoljstva in nižjih stroškov. To razumevanje mora biti vključeno v organizacijo, oblikovanje smernic, postopke ter v vsak stik strokovnjakov z družino.

BACKGROUND The Acute Lymphoblastic Leukemia Inter-Continental (ALL-IC) Study Group is currently conducting its 3rd academic randomized study to treat first-line pediatric ALL. By standardizing and continuously updating therapeutic guidelines and employing flow cytometry-based minimal residual disease (MRD) for treatment stratification, patient outcomes have improved. Nevertheless, relapse occurs in 10-20% of cases. When examined in 2014, survival rate of relapses fell short of benchmarks set by top-tier published studies. OBJECTIVES To establish a unified treatment framework for children experiencing their first relapse of ALL across the ALL-IC network. To analyze the post-relapse outcomes of these children and report findings from an observational registry trial. METHODS The IntReALL 2010 protocol was adapted to best fit ALL-IC countries. Patients were stratified as standard-risk (SR) or high-risk (HR) based on relapse characteristics and genetic profiles. High-risk criteria included T-cell immunophenotype, very early relapse, early isolated bone marrow relapse, relapse post-SCT, and specific genetic alterations. Standard-risk was assigned to all others. Allogeneic stem cell transplant (SCT) eligibility was extended to all HR patients, and among SR patients to those with poor response (marrow flow MRD ≥ 0.1% on induction day 29). Data were collected using an open-access registry on the REDCap platform. RESULTS Not all full-member groups of the frontline ALL-IC trials participated in this project or filled the registry. However, some observer countries did. Argentina (GATLA group), Bulgaria, Chile, Greece, Hungary, Romania, Slovenia and Turkey registered cases. To our knowledge, the ALL-IC REL protocol has also been used in Armenia, Bosnia-Herzegovina, Croatia, Georgia, Lebanon, Montenegro, Russia, Serbia, and Ukraine, though these countries didn't contribute to the registry. Recently, additional countries from the Middle East have shown interest. Of the 500 registered patients, 473 were included (median age 8.2 years, range 0.8 to 21; 38% female). Regarding immunophenotype, 47 T-ALL and 2 MPAL cases were there besides 424 B-ALL children. At initial diagnosis, 91% received ALL IC-BFM 2009 protocol treatment. Among relapses, 25.2% occurred very early, 31.5% early, 43.3% occurred late. CNS involvement was identified in 23.9% of the relapses, and testicular involvement in 4.2%. Upon relapse, 48% of patients were classified as SR and 52% as HR. Post-induction, complete remission rates were 73% in SR and 48% in HR groups. End of induction MRD < 0.1% was achieved by 52.2% of SR and 28.7% of HR patients. The 2-year overall survival rate was estimated at 55% for all patients, with 86% for SR and 26% for HR groups. Notably, the HR group faced a stark prognosis with significant mortality attributed to disease progression, treatment related complications and post-transplant complications. A surprisingly low proportion (39%) of HR patients were treated with SCT, likely due to limited or difficult access to this procedure. Among HR patients who did not receive SCT, there were virtually no long-term survivors. CONCLUSION This inaugural report from the ALL-IC REL Consortium highlights the promising outcomes for SR patients within our middle-income countries, paralleling those observed in the IntReALL study consortium. However, outcomes for the HR group fall much below the results of the ALL REZ BFM 2002 trial's HR arm - partly due to limited access to SCT in some regions. At other centers, integrating novel therapies, particularly immunotherapies, into the ALL-IC REL 2024 protocol may reduce leukemia-related and toxic death rates.

BACKGROUND:Flow cytometry plays is important in the diagnosis of acute lymphoblastic leukaemia (ALL) and when antigen-specific immunotherapy is indicated. We have investigated the effects of prednisolone, vincristine, daunorubicin, asparaginase and methotrexate on the antigen expression on blast cells that could influence the planning of antigen-specific therapy as well as risk-based treatment assignment. PATIENTS AND METHODS:Patients aged ≤ 17 years with de novo B-cell ALL (B-ALL) were enrolled in the study. Blast cells were isolated and exposed in vitro to 5 individual cytotoxic drugs in logarithmically increasing concentrations. Then, the expression of CD10, CD19, CD20, CD27, CD34, CD45, CD58, CD66c and CD137 antigens was determined by quantitative flow cytometry. RESULTS:Cytotoxic drugs caused dose-dependent or dose-independent modulation of antigen expression. Daunorubicin caused a dose-dependent down-modulation of CD10, CD19, CD34, CD45 and CD58 and an up-modulation of CD137. Vincristine caused a dose-dependent down-modulation of CD19 and CD58 and an up-modulation of CD45. Daunorubicin also caused dose-independent down-modulation of CD27 and prednisolone down-modulation of CD10, CD19, CD27, CD34 and CD58. Down-modulation of CD20 was detected only in relation to the specific dose of daunorubicin. CONCLUSIONS:The results of the study have shown that cytotoxic drugs can alter the expression of antigens that are important for immunotherapy. Importantly, daunorubicin, prednisolone and vincristine caused down-modulation of CD19 and CD58, suggesting that these drugs are better avoided during bridging therapy prior to bispecific antibodies or CAR-T cell therapy. In addition, immunophenotypic changes on blast cells induced by different drugs could also influence risk-based treatment assignment.

In this study, we aimed to identify patients within our B-ALL cohort with altered PAX5. Our objective was to use a comprehensive analysis approach to characterize the types of genetic changes, determine their origin (somatic/germline), and analyze the clinical outcomes associated with them. A consecutive cohort of 99 patients with B-ALL treated at the Children’s Hospital of the UMC Ljubljana according to the ALL IC-BFM 2009 protocol was included in our study. We used RNA sequencing data for gene expression analysis, fusion gene detection and single nucleotide variant identification, multiplex-ligation dependent probe amplification for copy number variation assessment, and Sanger sequencing for germline variant detection. PAX5 was impacted in 33.3% of our patients, with the genetic alterations ranging from CNVs and rearrangements to SNVs. The most common were CNVs, which were found in more than a third of patients, followed by point mutations in 5.2%, and gene rearrangements in 4.1%. We identified eight patients with a PAX5-associated genetic subtype that were previously classified as “B-other”, and they showed intermediate outcomes. We showed higher minimal residual disease values at the end of induction and poorer event-free survival in hyperdiploid cases carrying duplications in PAX5 compared to other hyperdiploid cases. We also report an interesting case of a patient with PAX5::FKBP15 and a pathogenic variant in PTPN11 who underwent an early relapse with a monocytic switch. In conclusion, this study provides valuable insights into the presence, frequency, and prognostic significance of diverse PAX5 alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes.

BACKGROUND In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is associated with increased risk of relapse. Traditionally, CNS involvement has been staged using cell counting and microscopic cytomorphological assessment of centrifuged and stained samples (cytospins) of the cerebrospinal fluid (CSF). More recently CSF flow cytometry has been shown to be more sensitive than cytology and to have prognostic significance. CNS staging is a basis for treatment stratification worldwide. CSF diagnostic protocols of study groups differ in small details, however, larger variability in practice was suspected based on informal discussions within the childhood ALL community. AIMS To systematically evaluate real world practice of CSF diagnostics and staging in pediatric ALL patients across hospitals globally. METHODS A survey was developed and distributed in 2021-2022 with target hospital categories and hospital numbers per country. Questions focused on numerous details of routine practice at the given hospitals in year 2021. RESULTS Eighty-two centers from 47 countries across five continents responded with a median 20 new pediatric ALL patients per year per center. Significant heterogeneity was observed in testing methodologies and CNS staging. The staging LP is contraindicated by high peripheral WBC, with threshold varying between 50 and 200 x109/L in 46% of the centers, while 54% of the centers set no threshold (LP is performed even in case of extreme leukocytosis). The timing of staging LP relative to the initiation of systemic antileukemic therapy also varies, with 57% of hospitals performing the LP strictly before therapy, while others routinely allowing some (1 and 7 days depending on hospital) systemic steroid and/or chemotherapy before. There is heterogeneity in the selection of test modalities to analyze the CSF. Manual cell counting is applied in 73%, automated cell counting in 43%, cytospins in 84% and flow cytometry in 33% of the hospitals during routine CNS-staging. Ten percent of the centers use only one modality, 54% of them use 2 modalities. A larger proportion of centers in high income countries analyze WBCs in cytospins routinely as compared to centers in middle income countries (92% versus 65%, p = 0.006). A similar trend was observed regarding CSF flow cytometry (39% vs 17%, p = 0.07). Similarly, a heterogenous set of testing modalities and cut offs/definitions are applied for CSF red cell quantification and for defining traumatic LP (TLP). Among hospitals which assess cytospins, the CSF volume centrifuged to prepare these specimens varies between 15 and 3000 microliters. Typical CSF volumes analyzed by flow cytometry range between 200 and 4000 microliters. There is also wide variation regarding the cut-off blast numbers to define positive findings in case of cytospins (≥1 to ≥5 cells) and flow cytometry (1 to 50 events characterized as test positivity in different centers). Interestingly, there is no correlation between the CSF volume used and the minimum number of blasts to define the tests' positivity. These heterogeneities are seen both within study groups and within individual countries in the same study group. DISCUSSION The above inconsistencies and differences in practice must have obvious clinical implications by significantly impacting CNS staging and thus CNS1/2/3/TLP frequencies and therefore treatment decisions for ALL patients worldwide. Moreover, internationally well-connected, larger pediatric oncology centers involved in research are thought to be overrepresented among survey participants. In view of this bias, global diagnostic heterogeneity can be larger and the quality of diagnostics poorer for a large proportion of patients than what our survey reflects. These results raise concern over published findings on the prognostic value of leukemic CNS involvement, particularly the CNS2 stage, and the comparability of published studies. We propose that details on CNS staging methods and adherence to the diagnostic guidelines should be included in publications of clinical studies. There is an urgent need for standardization, ideally through the development of international consensus guidelines in this field.

Immunosuppressive therapy (IST) combining antithymocyte globulin (ATG) and cyclosporine (CSA) is a consolidated therapy for aplastic anemia (AA). Currently, there are two animal sources of ATG available, namely horse (h-ATG) and rabbit (r-ATG) ATG. While the h-ATG Atgam® (Pfizer) continues to be the standard ATG for IST in the US, the h-ATG traditionally used in Europe and Asia, Lymphoglobulin® (Genzyme), was withdrawn from the market in 2007. Since then, first-line therapy in many European and Asian countries consisted of Thymoglobulin® (r-ATG, Sanofi). Several groups reported inferior results of IST with r-ATG compared to those with h-ATG, while comparable results of both ATG were reported by others group.1-3 Importantly, a randomized controlled trial published in 2011 showed an inferior response rate at 6 months (37% vs. 68%, p < .001) and a decreased overall survival (OS) at 2 years (76% vs. 96%, p = .04) in patients in the United States treated with r-ATG (Thymoglobulin®) compared with h-ATG (Atgam®).2 Based on these results, most European centers introduced Atgam® as first line IST, while Thymoglobulin® continues to be applied in countries where h-ATG is not available. Recently, Atgam® has been approved for the treatment of AA in most European countries. Here, we report the outcome of IST with ATG and CSA in 150 children with AA from 19 European countries, who were registered to the European Working Group of Severe Aplastic Anemia (EWOG-SAA) 2010 study between 2011 and 2020 (German Clinical Trials Register: DRKS00000610), comparing h-ATG Atgam® and r-ATG Thymoblobulin®. Our results show that patients treated with h-ATG have better early response, which may be clinically beneficial for patients with AA, while there was no difference in survival between the two ATG groups. One hundred-fifty consecutive patients with AA less than 18 years of age, who received first-line IST with either h-ATG (Atgam®, 40 mg/kg × 4 days, n = 110) or r-ATG (Thymoglobulin®, 3.5 mg/kg × 5 days, n = 40) with at least 180 days follow-up after start of treatment were included in this study. Patients with an HLA compatible sibling at diagnosis received a first-line hematopoietic stem cell transplantation (HSCT). A diagnosis of Fanconi anemia was excluded by a chromosomal breakage test. Patients with other inherited bone marrow failure syndromes were excluded from the study. h-ATG was the first choice of ATG, but r-ATG was used if h-ATG was not available. CSA was started on the first day of ATG administration and was slowly tapered (10% per month) at 12 months regardless of response status. Granulocyte-colony stimulating factor (5 μg/kg/day) was administered in the first 28 days to patients with <0.5 G/L neutrophils and was tapered and discontinued by day 60. Complete remission (CR), good partial remission (GPR), poor partial remission (PPR), no response (NR), and relapse were defined according to the criteria described in Supplementary Table 1.4 HSCT was recommended as a second-line therapy in all patients with non-response at day 180, relapse, or evidence of clonal evolution, while early HSCT (

Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well.To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia.We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.

Pediatric medical traumatic stress (PMTS) is a set of children's and their parents' psychological and physiological responses to pain, injuries, serious illnesses, and other experiences with the medical environment. Pediatric cancer patients have the highest prevalence of PMTS as the illness its treatment involve a set of stressors that trigger many negative psychological reactions. The current study examined the difference in levels of traumatic stress in children with cancer and their parents due to medical factors (type of cancer, outcome, duration, and intensity of treatment, time since diagnosis, relapse, and hospitalization in ICU). The study involved 183 parents of 133 children and 62 children and adolescents who were treated between 2009 and 2019 at the Clinical Department of Pediatric Hematology and Oncology of University Children's Hospital in Ljubljana. We collected the data using The Intensity of Treatment Rating Scale 2.0 [IRT-2], PTSD Checklist for Children/Parent [PCL-C/PR], The PTSD Checklist for DSM-5 [PCL-5] and The Child PTSD Symptoms Scale for DSM-5 [CPSS-5]. Traumatic stress symptoms are frequently present in both children and their parents, regardless of the cancer type, treatment duration, and treatment outcome. Children with relapse, children with more intensive treatment, and parents of the latter are at higher risk for PMTS occurrence. Additionally, we found a decreasing trend of traumatic responses after five or more years post-cancer diagnosis.