ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia.

Inter-individual variance in 6-mercaptopurine (6-MP) dose intensity is common in patients with acute lymphoblastic leukemia (ALL). We aimed to evaluate the association of common variants of ABCC4, ITPA, NUDT15, and TPMT with 6-MP dose intensity and toxicity in pediatric ALL patients. In this cohort, 13.8% of patients were intolerant to 6-MP with actual dosage less than 50% of scheduled dose. Twenty percent of patients were found to be heterozygous or homozygous mutated with NUDT15. NUDT15 c.415C > T and the genotype-predicted NUDT15 activity were significantly associated with 6-MP intolerance. TPMT*3C variants were not common in this cohort (2.8%). NUDT15 polymorphisms and genotype predicted NUDT15 activity were significantly associated with 6-MP dose intensity and leukopenia episodes. Combination of ABCC4 and ITPA variants (ABCC4 c.912G > T and ITPA c.94C > A) also showed significant positive association with 6-MP intolerance in Chinese children with ALL. Further study on pharmacogenetic screening for ALL patients to avoid 6-MP induced toxicity is recommended.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1973628.

Clinical Characteristics and Outcomes of Acute Childhood Encephalopathy in a Tertiary Pediatric Intensive Care Unit.

AIM: Childhood encephalopathy comprises a wide range of etiologies with distinctive distribution in different age groups. We reviewed the pattern of encephalopathy admitted to the pediatric intensive care unit (PICU) of a tertiary children's hospital. METHODS: We reviewed the medical records and reported the etiologies, clinical features, and outcomes of children with encephalopathy. RESULTS: Twenty-four admissions to the PICU between April 2019 and May 2020 were reviewed. The median (interquartile range) age was 10.0 (14.7) years and 62.5% were boys. Confusion (66.7%) was the most common presentation. Adverse effects related to medications (33.3%) and metabolic disease (20.8%) were predominant causes of encephalopathies in our study cohort. Methotrexate was responsible for most of the medication-associated encephalopathy (37.5%), whereas Leigh syndrome, pyruvate dehydrogenase deficiency and Wernicke's encephalopathy accounted for those with metabolic disease. The median Glasgow Coma Scale (GCS) on admission was 12.5 (9.0). Antimicrobials (95.8%) and antiepileptic drugs (60.9%) were the most frequently given treatment. Children aged 2 years or younger were all boys (P = 0.022) and had a higher proportion of primary metabolic disease (P = 0.04). Intoxication or drug reaction only occurred in older children. The mortality was 8.3%, and over half of the survivors had residual neurological disability upon PICU discharge. Primary metabolic disease (P = 0.002), mechanical ventilation (P = 0.019), failure to regain GCS back to baseline level (P = 0.009), and abnormal cognitive function on admission (P = 0.03) were associated with cerebral function impairment on PICU discharge. CONCLUSIONS: Primary metabolic encephalopathy was prevalent in younger children, whereas drug-induced toxic encephalopathy was common among older oncology patients. Survivors have significant neurologic morbidity. Failure to regain baseline GCS was a poor prognostic factor for neurological outcomes.

Double-unit unrelated cord blood transplantation for thalassemia major: Comparison with HLA-identical sibling bone marrow transplantation.

UCBT recipients with TM are at high risk of EF related to low number of stem cells and prior alloimmunization after multiple blood transfusions. Here, we evaluated the safety and efficacy of double-unit UCBT using TT-containing conditioning regimens in TM. Retrospective analysis of children who underwent double-unit UCBT for TM in the Prince of Wales Hospital between August 2007 and January 2017, and outcome of double-unit UCBT for TM was compared with outcome of HLA-matched sibling BMT. Ten patients, median age 4.2 years, received double-unit UCBT. All patients except one engrafted at a median of 19 days. None of the patients with successful engraftment had grade III or IV aGVHD. Among nine patients with successful engraftment, six of nine patients evaluable after day 100 developed cGVHD. All patients with cGVHD were well controlled after treatment with steroids and/or supportive care and maintained good quality of life. In comparison with patients receiving BMT, those given UCBT had slower platelet recovery, and more cGVHD. With a median follow-up of 272 months after BMT and 84 months after UCBT, the 8-year OS after BMT and UCBT was 92% and 90% (P = .84), whereas 8-year DFS after BMT and UCBT was 87% and 80% (P = .54). UCB could be an acceptable source of stem cells for transplantation of TM patients when HLA-matched family bone marrow donors are NA.

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

BACKGROUND: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis. OBSERVATION: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years. CONCLUSIONS: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.

Excellent outcome of acute lymphoblastic leukaemia with TCF3-PBX1 rearrangement in Hong Kong.

OBJECTIVE: The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3-PBX1 rearrangement. PATIENTS: All children in Hong Kong diagnosed with ALL with TCF3-PBX1 rearrangement over the past two decades were included. METHODS: Six hundred and twenty-four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3-PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event-free survival (EFS). RESULTS: The TCF3-PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3-PBX1 rearrangement, the 5-year overall survival and EFS for patients with TCF3-PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029). CONCLUSION: This population-based study over the past 20 years demonstrated that patients with TCF3-PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.

Hepatitis B infection acquired after haematopioetic stem cell transplant through horizontal mode.

A 22 month old child with thalassaemia major received unrelated umbilical cord blood transplantation. She was born to mother of HBsAg carrier and received hepatitis B immunoglobulin at birth and hepatitis B vaccination. She was HBsAg negative and anti-HBs positive before transplantation. After transplant, she was taken care by her mother and found to be HBsAg positive at 2 year post-transplant. Genotyping of the mother's and child's HBV status confirmed to be of same genotype and demonstrated horizontal transmission in post-transplant setting. Passive immunization of HBV may be considered in early post-transplant phase to prevent horizontal transmission of HBV, and antiviral treatment of the carer should be offered to prevent transmission of infection to immunocompromised child.

Perforin gene mutation in familial haemophagocytic lymphohistiocytosis: the first reported case from Hong Kong.

Familial haemophagocytic lymphohistiocytosis is a rare but invariably fatal disease without haematopoietic stem cell transplantation. Genetic defect identification is useful for confirming a clinical diagnosis, predicting the risk of future recurrence, and defining haemophagocytic lymphohistiocytosis predisposition in asymptomatic family members. Notably, familial haemophagocytic lymphohistiocytosis type 2 associates with mutations in the perforin gene (PRF1) which is the most frequent subtype of familial haemophagocytic lymphohistiocytosis. Although perforin gene mutations have been described in Asians, they are largely reported from Japan. The case reported here is the first familial haemophagocytic lymphohistiocytosis type 2 patient in Hong Kong with an identified perforin gene mutation.

Pathological fracture as the presenting feature in pediatric osteosarcoma.

BACKGROUND: Pathological fracture is an uncommon presentation in patients with long bone osteosarcoma. PROCEDURES: We retrospectively reviewed the database of all patients with histologically proven osteosarcoma under the age of 18 years from 1991 to 2011 in a tertiary pediatric oncology referral center. Five patients with pathological fractures as the first presentation of osteosarcoma were identified. The treatment strategies and complications were evaluated. Ten sex-, age-, and site- matched osteosarcoma patients without pathological fracture were selected as controls. The incidence of distant metastases and outcome, including local recurrence and survival, were compared between the index (with pathological fracture) and the control (without pathological fracture) groups. RESULTS: In the index group, all five patients were boys and the mean age of onset was 13.1 years (range 9.2-14.9). Three patients (60%, 3/5) received amputation and two (40%) had wide local excision of the tumor. Pathological fracture group showed higher rate of lung (60% vs. 10%, P = 0.04) and bone (60% vs. 10%, P = 0.04) metastases at presentation, and shorter overall 5-year survival (P = 0.04) than the control group. There was no significant difference of local recurrence (20%, P = 1.00) between these two groups regardless of the type of operation. CONCLUSION: Osteosarcoma complicated by pathological fracture as first presentation had higher incidence of lung and bone metastases at presentation and worse survival rate when compared with patients without pathological fracture.

Paediatric intra-axial posterior fossa tumours: pictorial review.

Paediatric brain tumours commonly arise in the posterior cranial fossa. Early diagnosis is often challenging due to initial non-specific clinical symptoms, especially in very young children. The typical MR features of tumours in this region including medulloblastoma, ependymoma, juvenile pilocytic subtype of cerebellar astrocytoma, brain stem glioma and atypical teratoid-rhabdoid tumour are illustrated. Diffusion-weighted imaging and apparent diffusion coefficient values combined with signal characteristics on conventional MR sequences can usually differentiate low-grade from high-grade tumours. Prompt diagnosis is crucial as total surgical resection, which is only possible in localised disease, improves prognosis. A practical MR flow chart is introduced for differentiating different types of posterior cranial fossa tumours, which might be useful in clinical practice.

Gorham-Stout disease: remission with sirolimus therapy.

Gorham-Stout disease (GSD) is a rare, non-hereditary, bone disease characterised by progressive osteolysis as a result of uncontrolled proliferation of endothelial-lined vessels replacing normal bone. We present a baby-girl with the classic radiological features of GSD and compatible clinical and histological findings, who developed progressive disease for over 2 years despite propranolol treatment. Propranolol treatment was stopped and sirolimus monotherapy started which resulted in near-complete resolution after 1 year, with no recurrence after discontinuation of treatment. This case not only illustrates the typical features of GSD on a variety of imaging modalities, but is also the first report showing stark contrast in response between propranolol and sirolimus treatment for GSD, highlighting how targeting lymphatic, rather than solely angiomatous, proliferation at the vascular endothelial growth factor-level may be a future direction.

Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia.

Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.

A pale Chinese boy with recurrent painful digital swelling.

Thalassaemia is the most common haemoglobinopathy in the Chinese population. However, recurrent painful digital swelling is not a typical manifestation of this well-known hereditary condition. We describe a case of co-inheritance of beta-thalassaemia and sickle cell trait in a Chinese family and a child who suffered from sickle cell/beta-thalassaemia with recurrent dactylitis. This report highlights awareness of this rare condition in the Chinese population, since acute manifestations can be life-threatening and mimic other emergency conditions. Prompt management can prevent further complications and avoid unnecessary interventions due to delay in diagnosis. A detailed family history and examination of the patient's peripheral blood smear is crucial to reach a correct diagnosis.

Pulmonary metastases in children with osteosarcoma: characteristics and impact on patient survival.

BACKGROUND: Approximately 15-20% of patients with osteosarcoma present with detectable metastatic disease and the majority of whom (85%) have pulmonary lesions as the sole site of metastasis. Previous studies have shown that the overall survival rate among patients with localized osteosarcoma without metastatic disease is approximately 60-70% whereas survival rate reduces to 10-30% in patients with metastatic disease. OBJECTIVE: To determine the incidence and characteristic features of pulmonary metastases in a group of osteosarcoma patients and correlate the findings with the prognostic outcome/survival. MATERIALS AND METHODS: Seventy-seven cases of histologically confirmed osteosarcoma were reviewed (47 male, 30 female, mean age 10.9). The site and size of the primary tumour and degrees of chemonecrosis were recorded. Lung metastases were analyzed according to their size, number, distribution and interval from diagnosis. The Kaplan-Meier method was used to analyze the survival probability curve. Significant differences (P < 0.05) were evaluated with the log-rank test for univariate analyses. RESULTS: Seventeen patients had synchronous and 11 had metachronous lung metastases. Sixteen (57%) underwent pulmonary metastasectomy. Nine of sixteen (56%) patients with metastasectomy and 10/12 (83%) patients without metastasectomy died. Poor chemonecrosis was associated with a worse outcome. Number, distribution and timing of lung metastases, but not the size of lung metastases, were of prognostic value for survival. CONCLUSION: Radiological detection of lung metastases is clinically important as it indicates a worse prognosis.

Malignant pigmented clear cell epithelioid cell tumor (PEComa) in an adolescent boy with widespread metastases: a rare entity in this age group.

Malignant pigmented clear cell epithelioid cell tumor of the kidney is a rare variant of perivascular epithelioid cells tumors (PEComa) or epithelioid angiomyolipoma (AML). PEComa is characteristically composed purely of epitheloid cells. The fat cells and the blood vessels that are typical of classic AML are absent. Most epithelioid AML cases are benign; however, malignant epithelioid AML of the kidney has been occasionally reported in adults in association with tuberous sclerosis. We report the radiological-pathological features of a malignant pigmented clear cell epithelioid renal tumor in a 15-year-old boy presenting with extensive metastases but without clinical evidence of tuberous sclerosis.

Primary pleomorphic liposarcoma of bone in an adolescent: imaging features of a rare entity.

We report a rare case of a primary osseous pleomorphic liposarcoma of the distal femur in a 13-year-old boy. Primary liposarcoma of bone is a very rare malignant tumour originating from primitive mesenchymal cells rather than mature adipose tissue. Pleomorphic liposarcoma is the least common of the eight known histological subtypes in the WHO classification. The entity is not previously reported in children. This is the third reported case of pleomorphic liposarcoma of the bone, and the first reported case presenting in adolescence. We describe the computed tomography and magnetic resonance imaging features of this rare bony tumour.

Continuous Renal Replacement Therapy (CRRT) for Nonrenal Indications among Critically Ill Children with Malignancy.

The role of continuous renal replacement therapy (CRRT) has been expanding beyond support for acute kidney injury (AKI) in recent years. Children with malignancy are particularly at risk of developing conditions that may require CRRT. We reported three children with malignancy who received CRRT for non-AKI indications. Patient 1 was a 17-year-old teenage girl who developed refractory type B lactic acidosis due to relapse of acute lymphoblastic leukemia (ALL). Her peak lactate level was 18 mmol/L, and the lowest pH and bicarbonate level was 7.13 and 6.0 mmol/L, respectively. She received three sessions of high-volume hemodiafiltration to bring down the lactate level. Patient 2 was a 15-year-old male with T-cell ALL who developed cytokine storm requiring mechanical ventilatory and high-dose inotropic support due to necrotizing enterocolitis complicated by pneumoperitoneum and Klebsiella pneumoniae septicemia. He received two sessions of hemoperfusion using a specific filter capable of endotoxin absorption and cytokine removal and was successfully weaned off all inotropes after the treatment. Patient 3 was an 8-year-old boy who received bone marrow transplantation and developed worsening hyperbilirubinemia and deteriorating liver function. He received a session of single-pass albumin dialysis for bilirubin removal prior to liver biopsy. Except for mild electrolyte disturbances, no major CRRT complication was encountered. Our report demonstrated that CRRT is an effective and safe procedure for a wide spectrum of nonrenal conditions among children with oncological diagnoses in the pediatric intensive care unit. However, the optimal dose, regime, timing of initiation, and monitoring target for these indications remain to be determined.

Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease.

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.

Inflammatory myofibroblastic tumour: an imaging dilemma (2010: 5b). IMFT of the bladder.

Inflammatory myofibroblastic tumour (IMFT) is a distinct entity under the group of inflammatory pseudotumours. Sometimes these pseudotumours can have an aggressive appearance on imaging, which makes it indistinguishable from other malignant neoplasms. We present a case of IMFT of the bladder in a child.

Radiological appearance of inflammatory myofibroblastic tumour.

Inflammatory myofibroblastic tumour (IMFT) is a distinct entity with variable clinical presentation and therapeutic options. We present three paediatric cases of IMFT, originated from the lung, bladder and ovary respectively. All lesions were heterogeneous, with mixed solid/cystic components and infiltrative pattern, and were interpreted as aggressive malignant neoplasms initially due to their bizarre imaging appearance. The definitive diagnosis was derived from characteristic histopathological features.