Remote Ischemic Conditioning in Pediatric Cancer Patients Receiving Anthracycline Chemotherapy: A Sham-Controlled Single-Blind Randomized Trial.

Background: Anthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection. Objectives: This randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy. Methods: We performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events. Results: A total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC (P < 0.001) and sham (P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias. Conclusions: RIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813).

Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong. METHODS: All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included. RESULTS: A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis. CONCLUSION: In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.

Outcome prediction of chronic myeloid leukemia (CML) in children.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

HLA alleles associated with asparaginase hypersensitivity in Chinese children.

Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)].

Neurological complications in Chinese children undergoing hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation, despite being a curative treatment for various pediatric disorders, is associated with significant acute and chronic complications. METHODS: This retrospective review of 196 hematopoietic stem cell transplantation episodes (144 allogeneic, 52 autologous) performed in a tertiary pediatric unit focused on neurological symptoms and complications occurred from the start of conditioning to within 3 years of transplantation. Indications for transplantation included both benign and malignant diseases. For episodes involving allogeneic transplantation, 42% of donors were matched-unrelated, 19% were matched-sibling, and 12% were haploidentical.  RESULTS: Neurological complications developed in 17% of all hematopoietic stem cell transplantation episodes. Tumors of central nervous system and leukemia or lymphoma were two indications reported to have higher incidence of 42% and 21%, respectively. The occurrence of neurological complications was significantly associated with primary diagnosis (p = 0.01), central nervous system involvement by underlying disease (p = 0.001), and radiation-based conditioning (p = 0.018). Upon multivariate analysis, central nervous system involvement by underlying disease remained to be the only significant factor (p = 0.019), while radiation-based containing conditioning (p = 0.029) is revealed to be associated when considering allogeneic transplantation alone. Pre-transplant central nervous system-directed treatment, allogeneic versus autologous donor, stem cell source, donor type, busulfan use, and cyclosporin use were not significantly associated with neurological complications. Patients with neurological complications were also found to have an inferior 2-year overall survival (53.9% ± 8.8% versus 63.8% ± 4.2%; p = 0.016). CONCLUSION: Neurological complications were common in pediatric hematopoietic stem cell transplantation and were associated with adverse outcome; non-radiation containing conditioning regimens might be beneficial in mitigating the risk of such complications.

Brain Microstructural Changes Associated With Neurocognitive Outcome in Intracranial Germ Cell Tumor Survivors.

BACKGROUND: Childhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors. METHODS: DKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof. RESULTS: The mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 - 98.8), which was below the age-specific normative expected mean IQ (P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls (P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions. CONCLUSION: Our study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT.

Circulating high-sensitivity troponin T and microRNAs as markers of myocardial damage during childhood leukaemia treatment.

BACKGROUND: We investigated whether plasma high-sensitivity cardiac troponin T (hs-cTnT) and circulating heart-associated microRNA (miRs) are increased in children with leukaemias during anthracycline-based chemotherapeutic treatment. METHODS: In vitro human pluripotent stem cell (hPSC)-derived cardiomyocyte model showed that miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from cells into culture medium in a time- and dose-dependent manner on doxorubicin exposure. Left ventricular (LV) myocardial deformation and circulating heart-associated miRs and plasma hs-cTnT during and after completion of chemotherapy were determined in 40 children with newly diagnosed acute leukaemia. RESULTS: Significant reduction of LV global longitudinal strain and strain rates were found within 1 week after completion of anthracycline therapy in the induction phase of treatment (all p < 0.05). Hs-cTnT level peaked and miR-1 increased significantly at this time point. Log-transformed hs-cTnT correlated negatively with LV global systolic longitudinal strain (r = -0.38, p < 0.001). Receiver operating characteristic analysis revealed that area under the curve for changes in plasma hs-cTnT from baseline and plasma miR-1 levels in detecting a reduction in ≥20% of global longitudinal strain were respectively 0.62 (95% CI 0.38-0.87) and 0.62 (95% CI 0.40-0.84). CONCLUSION: Plasma hs-cTnT and circulating miR-1 may be useful markers of myocardial damage during chemotherapy in children with leukaemias. IMPACT: Heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b,and miR-499 were increased in the culture medium upon exposure of hPSC-derived cardiomyocytes to doxorubicin. Only miR-1 increased significantly during anthracycline-based therapy in paediatric leukaemic patients. In paediatric leukaemic patients, plasma hs-cTnT and circulating level of miR-1 showed the most significant increase within 1 week after completion of anthracycline therapy in the induction treatment phase. The study provides the first evidence of progressive increase in circulating miR-1 and plasma hs-cTnT levels during the course of anthracycline-based therapy in children with leukaemias, with hs-cTnT level also associated with changes in LV myocardial deformation.

Congenital Hemolytic Anemia Because of Glucose Phosphate Isomerase Deficiency: Identification of 2 Novel Missense Mutations in the GPI Gene.

Glucose phosphate isomerase (GPI) deficiency is the second most common red blood cell enzymopathy involving the glycolysis pathway. It is an autosomal recessive disorder. Chronic hemolytic anemia is a common manifestation. The most severe one can present as hydrops fetalis. It can also be associated with neurologic dysfunction. We report a girl with severe hemolytic anemia at birth because of GPI deficiency. Enzyme activity assays were inconclusive because of previous blood transfusions. She was found to be compound heterozygous for 2 novel missense mutations, c.490C>A p.(Pro164Thr) and c.817C>T p.(Arg273Cys), in the GPI gene. Other than the chronic hemolytic anemia, she also has mild fine motor, gross motor delay, and developed cerebella ataxia since 5 years old.

Two- and three-dimensional myocardial strain imaging in the interrogation of sex differences in cardiac mechanics of long-term survivors of childhood cancers.

We aimed to interrogate sex differences in cardiac mechanics using two-(2D) and three-(3D) dimensional speckle tracking echocardiography (STE) in survivors of childhood cancers. 83 survivors (43 males) aged 25.6 ± 6.1 years at 16.0 ± 6.1 years after anthracycline therapy and 42 healthy controls (21 males) were studied. 2D STE was performed to assess LV linear deformation in three principal directions, while 3D STE was performed to assess LV ejection fraction, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). Receiver operating characteristic (ROC) curves were generated to to determine the usefulness of 2D and 3D echocardiographic indices to discriminate between survivors and controls. Survivors of both sex had significantly lower 2D and 3D strain indices compared with sex-specific controls (all p < 0.05). Among survivors, 2D GLS and GRS and all of the 3D indices were similar between males and females (all p > 0.05). Among cancer survivors, multivariate analysis revealed age at study (ß = - 0.26, p = 0.022) as a significant determinant of 3D GLS. The area under the ROC curve for 3D GLS was the largest at 0.89 amongst all 3D and 2D strain parameters, while that of 2D GLS was 0.83. For 3D GLS, a cut-off of 16.4% had a sensitivity of 85.7% and a specificity of 80.7% of differentiating survivors from controls. Notwithstanding the finding of impaired LV myocardial mechanics, the present study did not reveal evidence of sexual dimorphism in cardiac mechanics in long term survivors of childhood cancers.

Resting and exercise arterial dysfunction in anthracycline-treated adult survivors of childhood cancers.

BACKGROUND: Emerging evidence suggests potential arterial damage with the use of anthracycline-based chemotherapeutic regimens. We determined arterial function at rest and during exercise in anthracycline-treated adult survivors of childhood cancers. METHODS: Ninety-six adult survivors (54 males) aged 25.0 ± 5.9 years and 60 (30 males) healthy controls were studied. Central systolic blood pressure (cSBP) and radial augmentation index (rAI) was determined by applanation tonometry. Carotid arterial stiffness and intima-media thickness (IMT) were assessed using high-resolution ultrasound. RESULTS: At rest, survivors had significantly greater carotid IMT (p < 0.001) and stiffness index (p < 0.001), and higher cSBP (p = 0.037), rAI (p = 0.004) and rAI adjusted for a heart rate of 75/min (p = 0.009) than controls. At submaximal supine exercise testing, survivors had significantly greater percentage increase in carotid stiffness than controls (p < 0.001). Among survivors, 32 and 53% had respectively carotid IMT and exercise stiffness index exceeding normal (> + 2SD of controls). The slopes of increase in carotid IMT (p < 0.001) and exercise-induced changes in carotid stiffness (p < 0.001) with age were significantly greater in survivors than controls. Multivariate analysis revealed carotid IMT (ß = 0.32, p < 0.001) to be an significant correlate of dynamic percentage increase in stiffness index during exercise. CONCLUSIONS: Arterial dysfunction is evident at rest and worsens during exercise in anthracycline-treated adult survivors of childhood cancers.

Left Atrial Mechanics and Integrated Calibrated Backscatter in Anthracycline-Treated Long-Term Survivors of Childhood Cancers.

We tested the hypothesis that left atrial (LA) mechanics and myocardial calibrated integrated backscatter (cIB) are altered in anthracycline-treated long-term survivors of childhood cancers. Forty-nine survivors and 25 controls were studied. Survivors had significantly smaller maximal (p = 0.009) and minimal (p = 0.017) LA volumes and lower peak negative LA strains (p = 0.011). For left ventricular (LV) indices, survivors had significantly lower shortening fraction (p < 0.001), ejection fraction (p < 0.001) and mitral annular late diastolic velocity (p = 0.003). Myocardial cIB of the LA posterior wall, ventricular septum and LV posterior wall was significantly greater in survivors than controls (all p values <0.05). Peak negative LA strain was related to late diastolic mitral annular velocity (r = 0.27, p = 0.018), whereas LA cIB was related to the average of septal and LV posterior wall cIB (r = 0.54, p < 0.001). In conclusion, LA remodeling as characterized by contractile dysfunction and increased cIB suggestive of fibrosis occurs in adult survivors of childhood cancers.

Congenital intestinal fibrosarcoma with rapid recurrence requiring adjuvant chemotherapy.

A total of 16 cases of congenital fibrosarcoma have been reported from 1975 to March 2015. Five of the 16 had abnormal fusion between erythroblast transformation specific translocation variant 6 and neurotrophin recptor gene neurotrophic tyrosine kinase, receptor, type 3 (ETV6-NTRK3); in another five out of 16 this was absent, and six were not tested. All were managed by surgical resection but none involved metastasis. Herein we report the case of a newborn baby girl with congenital fibrosarcoma negative for ETV6-NTRK3 gene fusion, who presented with ileal perforation and positive resection margin. She had rapid recurrence with lymph node metastasis treated with postoperative chemotherapy. There was no further recurrence at >3 years of follow up.

Myocardial stiffness as assessed by diastolic wall strain in adult survivors of childhood leukaemias with preserved left ventricular ejection fraction.

AIMS: We tested the hypothesis that myocardial stiffness as assessed by diastolic wall strain (DWS) is altered in adult survivors of childhood leukaemias with preserved left ventricular (LV) ejection fraction and explored its association with myocardial fibrosis and diastolic deformation. METHODS AND RESULTS: Ninety-four (53 males) adult survivors of childhood leukaemias aged 22.2 ± 5.5 years and 66 (36 males) healthy controls were studied retrospectively. Diastolic wall strain and calibrated integrated backscatter (cIB) were measured as indices of myocardial stiffness and fibrosis, respectively. Left and right ventricular (RV) diastolic and torsional mechanics were interrogated using speckle tracking echocardiography. Patients had significantly lower LV DWS, and hence stiffer LV myocardium, and greater myocardial cIB in patients than controls (all P < 0.001). Left ventricular longitudinal, radial, and circumferential early diastolic strain rates, circumferential late diastolic strain rate, and peak twisting and untwisting velocities, tricuspid annular early diastolic velocity, and RV-free wall longitudinal early diastolic strain rate were significantly lower in patients than controls (all P < 0.05). Diastolic wall strain correlated inversely with myocardial cIB, and positively with LV longitudinal, radial, and circumferential early diastolic strain rates (all P < 0.05), while myocardial cIB correlated inversely with LV radial and circumferential early diastolic strain rates, circumferential late diastolic strain rate, peak twisting and untwisting velocities, and tricuspid annular e velocity (all P < 0.05). CONCLUSION: In adult survivors of childhood leukaemias, despite the preservation of LV ejection fraction, increased stiffness of the LV myocardium is evident and is associated with myocardial fibrosis and impaired ventricular diastolic function.

Autologous cord blood transplantation for metastatic neuroblastoma.

Auto-SCT is a common approach for metastatic neuroblastoma with the intention to rescue hematopoiesis after megadose chemotherapy. PBSC or BM is the usual stem cell source for auto-SCT. Auto-CBT for neuroblastoma has very rarely been performed. Currently, case reports are available for two patients only. We performed 13 auto-SCTs for high-risk neuroblastoma from 2007 to 2013, including four cases of metastatic neuroblastoma aged 11-64 months treated with auto-CBT. All four patients had partial or CR to upfront treatments before auto-CBT. Nucleated cell dose and CD34+ cell dose infused were 2.8-8.7 × 10(7) /kg and 0.36-3.9 × 10(5) /kg, respectively. Post-thawed viability was 57-76%. Neutrophil engraftment (>0.5 × 10(9) /L) occurred at 15-33 days, while platelet engraftment occurred at 31-43 days (>20 × 10(9) /L) and 33-65 days (>50 × 10(9) /L) post-transplant, respectively. There was no severe acute or chronic complication. Three patients survived for 1.9-7.7 yr without evidence of recurrence. One patient relapsed at 16 months post-transplant and died of progressive disease. Cord blood may be a feasible alternative stem cell source for auto-SCT in patients with stage 4 neuroblastoma, and outcomes may be improved compared to autologous PBSC or BM transplants.

Myocardial iron load and fibrosis in long term survivors of childhood leukemia.

BACKGROUND: We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. PROCEDURE: Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. RESULTS: None of the survivors had significant myocardial iron overload (T2*<20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-<55%) in 9% (5/58), while RV EF was abnormal (EF <45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P > 0.05). CONCLUSION: Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload.

A patient with mosaic neurofibromatosis type 2 presenting with early onset meningioma.

A female patient was found to have meningioma when she was 3 years and 11 months old and subtotal excision was performed. The residual tumour recurred 3 months after the first excision, and again 11 months after the second one. She was also found to have subcutaneous neurofibroma. However, her clinical features did not fulfil the diagnostic criteria for neurofibromatosis type 2 (NF2), and her family history was unremarkable. Considering that primary meningioma is extremely rare in the paediatric population, the diagnosis of NF2 was considered. It was thought that this might have an impact on her subsequent management. Genetic testing on blood DNA for NF2 was arranged, and the results confirmed that she had mosaic deletion of the promoter to exon 16 of NF2. With uncertainty of whether NF2 mutations are also present in other tissues, vigilant follow-up for other NF2-related complications would be required in the future.