Risk factors and disease trajectories of recurrent immune thrombocytopenia in children.

This retrospective study aimed to analyse the course and outcome of recurrent immune thrombocytopenia (ITP) in children and to identify factors associated with recurrence. A total of 497 newly diagnosed ITP children with platelet <30 × 109/L between January 1988 and December 2019 were included. Recurrent ITP was defined as a new event of thrombocytopenia after at least 3 months of remission without treatment. Twenty-nine (5.8%) children experienced 48 recurrent episodes. The median time from diagnosis to recurrence was 22 months. Most recurrences occurred in children aged 1.5-10 years with a recent infection history. Compared to non-recurrent ITP, children with recurrent ITP had delayed remission with lower platelets at 1 month and 3 months postdiagnosis. Multivariate analysis identified aged 1.5-10 years (hazard ratio [HR] 3.65, 95% confidence interval [CI]: 1.35-9.82) and delayed remission at 7-12 months (HR 4.04, 95% CI: 1.37-11.95) as predictors for recurrence. Most recurrent ITP patients had minor or mild symptoms, higher platelet counts, did not require treatment, and achieved remission within 12 months. The similar remission trajectories among the first and recurrent ITP, but different from the courses in the non-recurrent ITP, suggest that recurrent ITP might have a unique biological basis.

Predictors for spontaneous remission in childhood chronic immune thrombocytopenia.

This study examined the factors associated with spontaneous remission in children with chronic immune thrombocytopenia (ITP). We retrospectively analyzed the medical records of patients diagnosed with ITP from January 1988 to December 2019 at our institute. A total of 104 children with chronic ITP were identified. The median follow-up time from diagnosis of chronic ITP was 3.6 years (IQR 1.2-8.3, range 0.1-31.4). Fifteen (14.4%) patients with severe symptoms received specific platelet-elevating therapies, including splenectomy, rituximab, and thrombopoietin receptor agonists. Seven of them achieved remission. Among the patients with a platelet count < 30 × 109/L at the time of diagnosis of chronic ITP, those who received specific platelet-elevating therapies had a higher remission rate compared to those who did not (HR: 4.66, 95% CI: 1.36-16.0). Sixteen patients (15.4%) developed systemic lupus erythematosus, 46 (44.2%) still had thrombocytopenia after a median follow-up of 6.8 years, and 42 (40.4%) achieved remission with a median time to remission of 2.0 years (IQR 0.6-4.1, range 0.1-15.7). The two independent predictive factors for spontaneous remission in childhood chronic ITP were platelet counts > 30 × 109/L at the time of diagnosis of chronic ITP (HR: 3.16, 95% CI: 1.51-6.62) and persistently negative ANA at follow-up (HR: 6.12, 95% CI: 1.46-25.7). The cumulative probabilities of spontaneous remission at 10 years post-diagnosis of chronic ITP were 72.2% for patients without risk factor compared to 0% for patients with two risk factors.

Children with chronic myeloid leukaemia treated with front-line imatinib have a slower molecular response and comparable survival compared with adults: a multicenter experience in Taiwan.

BACKGROUND: The direct comparison of molecular responses of front-line imatinib (IM) monitored at the same laboratory between children and adults with chronic phase (CP) of chronic myeloid leukaemia (CML) had not been reported. In this multicenter study, we compared the landmark molecular responses and outcomes of paediatric and adult CML-CP cohorts treated with front-line IM in whom the BCR::ABL1 transcript levels were monitored at the same accredited laboratory in Taiwan. METHODS: Between June 2004 and July 2020, 55 newly diagnosed paediatric and 782 adult CML-CP patients, with molecular diagnosis and monitoring at the same reference laboratory in Taiwan, were enrolled. The criteria of 2020 European LeukemiaNet were applied to evaluate the molecular responses. RESULTS: By year 5, the cumulative incidences of IS <1%, MMR, MR4.0 and MR4.5 of paediatric patients were all significantly lower than those of adult patients (58 vs 75%, 48 vs 66%, 25 vs 44%, 16 vs 34%, respectively). The 10-year progression-free survival (PFS) (90%) and overall survival (OS) (94%) of paediatric patients did not differ from those (92%) of adult patients. CONCLUSIONS: We demonstrated the paediatric cohort had slower molecular responses to front-line IM and similar outcomes in 10-year PFS and OS in real-world practice.

Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Medical clowning influences the emotions of parents of children undergoing cancer treatment: A quasi-experimental study.

BACKGROUND: Medical clowning for children has been found to be effective at enhancing parents' psychological well-being during preoperative preparation, but has not been found during cancer treatment. This study aimed to examine whether and how medical clowning influenced the emotions of parents of children undergoing cancer treatment. METHODS: In this quasi-experimental study, 96 parents of children receiving inpatient cancer treatment were recruited, from June 2018 through April 2020. A demographic questionnaire measuring characteristics of parent and dyadic child, Brief Symptom Rating Scale measuring psychological distress of the parent, and Mood Assessment Scale measuring emotional status of parent and child were administered 1 day before a clowning service. The day after the clowning service, the Mood Assessment Scale again collected emotional status for parent and child. Descriptive analysis, bivariate analysis, and structural equation modeling to fit the actor-partner, cross-lagged model were used. FINDINGS: Parents experienced a low degree of psychological distress that called for emotional management. The indirect effect of medical clowning on parents' emotions through children's emotions was significant, as were the direct effect and total effect of medical clowning on parents' emotions. DISCUSSION: Parents experienced psychological distress during their child's inpatient cancer treatment. Medical clowning can directly improve children's emotions and through this pathway indirectly improve their parents' emotions. APPLICATION TO PRACTICE: There is need to monitor psychological distress and provide interventions for parents of children undergoing cancer treatment. Medical clowns should continue to serve parent-child dyads in pediatric oncology practice and become members of multidisciplinary health care teams.

Surgical treatment confers prognostic significance in pediatric malignant mediastinal germ cell tumors.

BACKGROUND: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. METHODS: The authors retrospectively reviewed children 0-18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. RESULTS: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0-17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5-year overall survival, 78% vs. 7%, p < .001). After comparing patients who received first-line cisplatin- and carboplatin-based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. CONCLUSIONS: Surgical treatment is recommended for mediastinal GCT. Cisplatin-based chemotherapy was not superior to carboplatin-based chemotherapy as first-line treatment and may be avoided due to toxicity concerns.

The effectiveness of a medical clowning program on improving emotional status among hospitalized children undergoing cancer treatment: A quasi-experimental study.

PURPOSE: To examine the effectiveness of one-time medical clowning on improving short-term positive emotions among hospitalized children undergoing cancer treatment, and to analyze whether age moderates this effect. DESIGN: In this quasi-experimental research study, we recruited a pooled sample of 96 children who were undergoing cancer treatment in pediatric oncology/hematology wards at three university-affiliated medical centers in Taiwan from June 2018 through April 2020. METHODS: Children's demographic characteristics, symptom distress, quality of life, and pretest emotional status were collected at T1. At T2, we collected only posttest emotional status. We adapted generalized estimating equation models to evaluate the effectiveness of medical clowning on enhancing positive emotions. FINDINGS: Changes in the probabilities of positive emotion were significantly different across groups (51.84% for the experimental group, 15.76% for the control group; Δ = 36.08, p = 0.001), and the change was more than two times larger for the experimental group (effect ratio = 3.28, p < 0.05) than for the control group. When evaluating the moderating effect of age on the intervention, none of the coefficients reached the significant (p < 0.05) levels, suggesting that age may not moderate the intervention effect. CONCLUSION: This study demonstrates the core value of medical clowning in child-friendly health care. Our findings clearly support the benefit of the one-time medical clowning program on enhancing short-term emotional well-being across age groups of children. Medical clowning programs should be strongly encouraged and supported in pediatric oncology wards. CLINICAL RELEVANCE: Medical clowning programs should be widely and continuously implemented in pediatric oncology wards as a routine clinical practice for enhancing emotional well-being among children receiving cancer treatment. Nurses need to be aware of medical clowning's equal effectiveness across age groups, not only or better for younger children.

Lymphoma-based therapy for refractory or relapsed Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in children.

Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome. Although etoposide-based immunochemotherapy has improved survival rates, consensus regarding the appropriate salvage therapy for patients with refractory or relapsed EBV-HLH is lacking. We performed a retrospective study to examine the efficacy of a lymphoma-based treatment regimen for children with refractory or relapsed EBV-HLH. The data of six children were analyzed. Four had cytogenetic abnormalities, and two experienced a transition to EBV-positive T-cell lymphoma. They were treated with an intensive chemotherapy regimen modified from that used in the Berlin-Frankfurt-Münster Group Trial as salvage therapy. Five patients (83%) achieved complete response. Four patients (67%) were disease free for a median of 10 years without undergoing allogeneic hematopoietic stem cell transplantation. No grade 3 or 4 nonhematologic adverse events occurred. Lymphoma-based chemotherapy is a potential curative treatment for some subgroups of children with refractory or relapsed EBV-HLH.

Outcome of young adult patients with very-high-risk acute lymphoblastic leukemia treated with pediatric-type chemotherapy - a single institute experience.

BACKGROUND/PURPOSE: Adult patients of acute lymphoblastic leukemia (ALL) with very high-risk (VHR) characteristics have an inferior outcome, and allogeneic hematopoietic stem cell transplantation (HSCT) is usually performed. In contrast, VHR pediatric patients can be treated effectively with minimal residual disease (MRD)-guided pediatric protocols and HSCT are not always needed. METHODS: We retrospectively reviewed young adult ALL VHR patients treated with the pediatric-type (TPOG-ALL-2002 VHR) regimen in our institute from 2008 to 2019 and compared the event-free survival (EFS) with patients treated with an adult-type regimen (Hyper-CVAD alternating with high dose methotrexate and cytarabine). RESULTS: We identified 16 patients treated with the TPOG and 11 treated with the Hyper-CVAD regimen. Philadelphia chromosome-positive (n = 10) and T-cell immunophenotype (n = 11) are the most common VHR features. Compared with the Hyper-CVAD group, patients treated with the TPOG regimen showed a trend toward better EFS with a hazard ratio (HR) of 0.42 (p = 0.16). Compared with untransplanted patients, HSCT showed a positive trend in the Hyper-CVAD (HR 0.22, p = 0.12) but not in the TPOG group (p = 0.37). Untransplanted patients treated initially with the hyper-CVAD regimen had a significantly worse outcome than the TPOG regimen (HR 4.19, p < 0.05). In the TPOG group, patients with negative MRD at the end of consolidation had a significantly better outcome (HR 0.12, p = 0.03). CONCLUSION: Young adult VHR patients can be effectively treated with the TPOG-ALL-2002 protocol, and those who achieved MRD negativity before the end of consolidation have a good outcome without allogeneic HSCT.

Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.

BACKGROUND: Patients with childhood cancer are at increased risk for the development of second cancers. METHODS: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. RESULTS: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. CONCLUSION: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.

Rhabdomyosarcoma in a child with nephrotic syndrome treated with cyclosporine: a case report with literature review.

BACKGROUND: In patients with frequently relapsing nephrotic syndrome, immunosuppressive therapy such as cyclosporine are often required to maintain remission. Cyclosporine has been noted to have tumorgenesis effects. In this case report, we present a child with relapsing nephrotic syndrom developed a rhabdomyosarcoma on her tongue after adout 4 years of continual immunosuppressive therapy. CASE PRESENTATION: A 2-year-old female child had nephrotic syndrome (urine protein-creatinine ratio 749.1 mg/mg; blood urea nitrogen 11 mg/dL; serum creatinine 0.3 mg/dL; and serum albumin 1.8 g/dL.) Proteinuria resolved on treatment with daily prednisolone for 4 weeks at the dose of 45 mg (2.5 mg/kg/day) but recurred with taper from 25 mg/day to 10 mg/day. At least five more episodes of relapse occurred within about a 3-year period. After the third relapse, she was treated with prednisolone and cyclosporine (at initial dose of 50 mg/day [1.7 mg/kg/day]) for immunosuppression. About 4 years after the diagnosis of nephrotic syndrome had been made, an embryonal rhabdomyosarcoma developed on her tongue. The cancer was treated with TPOG-RMS-LR protocol, with vincristine, actinomycin, and cyclophosphamide. Magnetic resonance imaging scan, performed about 3 years after the start of TPOG-RMS-LR therapy, revealed complete remission of the cancer. CONCLUSIONS: Although treatment with cyclosporine cannot be conclusively implicated as the cause the rhabdomyosarcoma in this patient, the association should prompt consideration of its use in the treatment of frequently relapsing nephrotic syndrome in children.

Incidence and treatment outcome of aplastic anemia in Taiwan-real-world data from single-institute experience and a nationwide population-based database.

Aplastic anemia (AA) is a rare disease characterized by pancytopenia and bone marrow failure. The incidence of AA tends to be higher in Asia than in the West, but real-world data about AA in Asia remain limited. We aimed to describe the basic data, treatment, and outcome of AA patients from our institute and evaluate the incidence of AA in Taiwan with a nationwide population-based cohort from National Health Insurance Research Database (NHIRD). We identified patients older than 2 years with AA in the Registry of Catastrophic Illness of NHIRD between 2001 and 2010 and excluded patients with any diagnosis suggestive of congenital or secondary bone marrow failure. With a total of 1270 patients, the overall incidence was 5.67 per million people per year, and there was a biphasic age distribution of incidence rate, highest in ≥ 70 years (19.83 per million people per year) and another peak at age 2-9 years (5.26 per million people per year). Overall, the 5-year survival was 60.0%. Hematopoietic stem cell transplantation (HSCT) and anti-thymocyte globulin-based immunosuppressive therapy (IST) were the major first-line treatments in patients younger than 40 years and were linked with good survival. In contrast, the majority of patients older than 60 years were treated with androgen, and the survival was poor. In multivariate analysis, "severe AA," "very severe AA," and "treatment other than HSCT, IST, or androgen" were independent risk factors for inferior survival. In conclusion, the incidence of AA in Taiwan is consistent with nearby Asian countries and is higher than in the West. Advanced age is associated with higher incidence and poorer outcome.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.

BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. RESULTS: In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. CONCLUSIONS: For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan.

BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. PROCEDURE: In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). RESULTS: Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. CONCLUSIONS: With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors.

Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC50 of ∼10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 µM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients.

Predictors of Remission in Severe Childhood Immune Thrombocytopenia.

Childhood immune thrombocytopenia (ITP; platelet count < 100 × 109/L) is the most common bleeding disorder in children. A total of 3-5% of children with ITP face a greater risk of bleeding, resulting in significant morbidity and mortality. Childhood ITP is often benign and self-limited; however, children with severe ITP (platelet count < 30 × 109/L) require investigation and monitoring. In addition, 20% of ITP patients may not go into remission (platelet counts < 100 × 109/L by 12 months after diagnosis) and may develop chronic ITP. The early identifying predictors associated with the resolution of severe ITP at the time of diagnosis may be helpful for family guidance. However, there is still controversy about the associations between the clinical factors at the time of initial diagnosis and the definitions of disease remission assessed at different timepoints after diagnosis. This retrospective study aimed to analyze the shared clinical factors among the disease remission definitions at three arbitrarily set timepoints-3, 6, and 12 months after diagnosis. This study retrieved records for hospitalized children aged under 18 years and diagnosed with ITP from the hospital registry in a tertiary university hospital. Clinical variables were recorded by reviewing the medical records with structured data entry for ITP admission. The serial follow-up platelet counts within 12 months after diagnosis were recorded. The times of ITP remission were identified by experienced pediatric hematologists. Patients with mild-form ITP (platelet counts ≥ 30 × 109/L) at diagnosis or who were lost to follow-up within 3 months were excluded. From 1988 to 2019, 546 children were enrolled, and a total of 497 children with severe ITP were included in the further analysis. In total, one (0.2%) died of an intracranial hemorrhage, 363 (73.2%) children went into remission at 3 months, 40 (8.1%) went into remission between 6 and 12 months, and 104 (20.9%) developed chronic ITP. The shared significant predictors for remission by the third, sixth, and twelfth months included pre-adolescent age (<10 years) at diagnosis, abrupt onset (duration of symptoms prior to admission ≤ 2 weeks), and speedy recovery (platelet count > 100 × 109/L at 1 month post diagnosis). ITP patients with positive viral serology tests or vaccination within 4 weeks had trends of delayed remission. In conclusion, diagnosis before preadolescent age, abrupt onset, and speedy recovery may share favorable factors for the remission of childhood ITP assessed at different timepoints.

A case series and literature review on 98 pediatric patients of germ cell tumor developing growing teratoma syndrome.

INTRODUCTION: Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on the clinical characteristics and outcomes of GTS in children with MGCTs are limited. METHODS: We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS. RESULTS: The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety-five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event-free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5-year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001). CONCLUSION: For patients with high-risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy.

Hypoalbuminaemia is an independent predictor for hemophagocytic lymphohistiocytosis in childhood Epstein-Barr virus-associated infectious mononucleosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition in children with Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). This study aimed to identify commonly available clinical and laboratory predictors that might help clinicians decide to perform the bone marrow and immunological tests for HLH in paediatric EBV-associated IM. METHODS: A retrospective case-control study of patients aged <18 yr diagnosed with EBV-associated IM and HLH from 1991 to 2010 in a tertiary medical centre was conducted. A diagnosis of HLH was defined as fulfilling the criteria of the guidelines of the HLH-2004 protocol of the Histiocyte Society and consisted of at least evidence of hemophagocytosis in a bone marrow biopsy. RESULTS: A total of 177 IM and 27 HLH patients were enrolled. The mean age was 5.3 yr with a female-to-male ratio of 1.06. The most common characteristics (>70% of patients) were fever, lymphadenopathy and hepatomegaly. In addition to the diagnostic criteria of HLH including fever, splenomegaly, cytopenia, hyperferritinaemia, hypertriglyceridemia and/or hypofibrinogenaemia, children with HLH had a significantly higher rate of prolonged fever >10 d, hepatomegaly, jaundice, general malaise, elevated aspartate aminotransferase, lactate dehydrogenase, C-reactive protein and hypoalbuminaemia compared to those with IM (all P < 0.01). Multiple logistic regression confirmed that hypoalbuminaemia (OR = 23.1, P = 0.01) was an independent predictor of paediatric HLH, with a high sensitivity (96%) and a good negative likelihood ratio (0.06) in patients with EBV-associated IM. CONCLUSIONS: Hypoalbuminaemia is a unique characteristic and potentially a valuable predictor for HLH in paediatric EBV-associated IM.

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia.

BACKGROUND: The absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T-cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T-cell ALL. PROCEDURE: Forty-five children with T-cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q-PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q-PCR was defined as a fold-change <0.35. RESULTS: ABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23-53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10-16.42). CONCLUSIONS: The absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T-cell ALL in Taiwan. Providing patients with T-cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials.