A higher CD34 + cell dose correlates with better event-free survival after KIR-ligand mismatched cord blood transplantation for childhood acute myeloid leukemia.

Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.

Association of albuminuria with kidney function and hemodynamic disturbance in pre-school children who undergo congenital heart disease surgery.

BACKGROUND: We validated the prevalence of albuminuria and its association with kidney function and hemodynamics in pre-school children who underwent surgery for congenital heart disease (CHD). METHODS: From 403 patients who had undergone surgery for CHD at least 6 months before pre-school and were admitted to our hospital between 2011 and 2015, 75 who underwent blood and urine tests and cardiac catheterization were included in this study. The urinary albumin-to-creatinine ratio (ACR) was quantified, and the relationship of ACR with physical and laboratory findings and hemodynamics assessed using cardiac catheterization was analyzed. RESULTS: The study cohort was divided into three groups: Fontan group (n = 25), tetralogy of Fallot (TOF) group (n = 18), and control group (other biventricular CHDs; n = 32). The median age of patients was 5.9 years. ACR was higher in the Fontan group than in the TOF and control groups (median: 15.0 vs. 5.0 and 0.0 mg/g, p < 0.001). Moreover, albuminuria (ACR > 30 mg/g) was observed in 20.0% of Fontan patients, while ACR was associated with potential complicating factors of Fontan circulation: high central venous pressure, high mean pulmonary artery pressure, and worse than moderate atrioventricular regurgitation. ACR showed a moderate correlation with the cystatin C-based estimated glomerular filtration rate (r = - 0.725, p < 0.001). CONCLUSIONS: Measurement of albuminuria in Fontan patients before they join elementary school is useful because it reflects kidney function and hemodynamic factors that can worsen their condition. Identification and management of patients with albuminuria may facilitate early therapeutic intervention for worsening Fontan factors, eventually delaying the deterioration of kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Case Report: The leopard sign as a potential characteristic of chronic granulomatous disease-associated colitis, unrelated to colitis severity.

Background: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. Methods: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. Results: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. Conclusion: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.

Association Between Airway Stenosis Degree and Respiratory Distress in Infants With a Vascular Ring.

Background Although the number of cases of prenatally diagnosed vascular rings is increasing, some cases may remain asymptomatic, and no indicator of the appearance of dyspnea has been established. Thus, we aimed to determine the relationship between the degree of airway compression by the vascular ring on contrast-enhanced computed tomography (CT) and respiratory distress. Methods This is a retrospective study of nine patients diagnosed with vascular rings at a single hospital from July 2010 to December 2019. Data regarding the patient's clinical characteristics, such as prenatal diagnosis, vascular ring type, complicated cardiac disease, and presence or absence of surgery, were recorded. Airway assessment on contrast-enhanced CT was measured in the axial cross-section. Statistical analysis was performed using Statistical Product and Service Solutions (SPSS) (version 25.0; IBM SPSS Statistics for Windows, Armonk, NY). Results Five of the eight patients had respiratory distress. Patients with respiratory distress were less likely to have been diagnosed prenatally (p = 0.04) and had smaller stenosis degree of anteroposterior diameter (p = 0.03). Conclusion Contrast-enhanced CT is useful in patients with vascular rings. Our study suggests that the stenosis degree of the anterior-posterior diameter of the airway is related to dyspnea.

A successful treatment for chronic active Epstein-Barr virus disease with Nephrotic Syndrome.

Chronic active Epstein-Barr virus (CAEBV) disease is more likely to occur when a patient is on immunosuppressive therapy for any disease or is susceptible to infection, and the prognosis is poor without appropriate treatment, including hematopoietic stem cell transplantation (HSCT). In addition to HSCT, several other chemotherapy regimens have been reported, but all of them are difficult to maintain in remission. Without HSCT, survival rates have been reported to be 50% in 5 years and 25% in 15 years. This is a report of a 13-year-old boy who developed CAEBV disease during cyclosporine A (CyA) treatment for the steroid-dependent nephrotic syndrome (SDNS). Since SDNS precluded HSCT or chemotherapy, CyA was tapered off based on the belief that alleviating his immunosuppressed state would decrease the CAEBV disease. We decided to gradually reduce the CyA dose to activate T-cell immunity, while periodically monitoring the EBV viral load. Finally, we found an appropriate dose that could suppress both CAEBV disease and SDNS, and it lasted for more than 9 years. No case has been reported to date in which a patient developed CAEBV disease while receiving immunosuppressive drugs for the primary disease, and both diseases were controlled only by reducing the dose of immunosuppressive drugs. In this report, we show that dose reduction of immunosuppressive agents without chemotherapy or HSCT is an effective option for the treatment of CAEBV disease in patients receiving immunosuppressive agents.

Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group.

In Asia, a few countries have a long and established history of collaborative clinical trials successfully formed national children's cancer study groups, but many still do not have such groups. The process of forming national children's cancer groups is fraught with many hurdles, which varies among the countries. One of the basic requirements for running clinical trials is an affordable health care system in which most of the children with cancer can receive the proposed treatment. The health insurance coverage for children with cancer varies from <20% to as high as 100% among Asian countries, and the operation of clinical trials must also be adjusted accordingly. Shortage of research personnel is common, including medical, nursing, research coordinators, and data managers. The establishment of the Asian Pediatric Hematology and Oncology Group aims to provide a good platform for promotion of international clinical trials in the Asian countries.

Preoperative and Intraoperative Risk Factors for Surgical Site Infection in Pediatric Cardiac Surgery.

BACKGROUND: Surgical site infection (SSI) is a major complication of pediatric cardiac surgery. If the risk of developing SSI can be predicted based on the patient's preoperative background, appropriate preoperative management to prevent the development of SSI can be achieved. METHODS: We retrospectively studied cases for patients younger than 7 years of age among surgeries performed through a median sternotomy at Kagoshima University Hospital from April 2011 to March 2021. SSI was diagnosed according to the Centers for Disease Control and Prevention guidelines and classified into 3 types: superficial incisional SSI (SiSSI), deep incisional SSI (DiSSI) and mediastinitis. RESULTS: Of the 765 consecutive pediatric cardiac surgeries, 597 were included in the analysis based on the exclusion criteria. Of these, 17 (2.8%) developed SSI (3 SiSSI cases, 2 DiSSI cases and 12 mediastinitis cases), with Staphylococcus aureus as the major pathogen. Univariate analysis revealed that low preoperative serum protein ( P = 0.049) and low serum albumin levels ( P = 0.023) were risk factors for the development of SSI. No findings suggested impaired hepatic synthesis, inflammatory disease or protein loss from the kidney or intestinal tract. We concluded that malnutrition caused low serum protein and albumin levels. CONCLUSIONS: Low preoperative serum protein and albumin levels are risk factors for SSI development of SSI. Nutritional status should be regularly assessed in children scheduled for cardiac surgery, and interventions, such as nutritional guidance, should be considered if malnutrition is suspected.

Refractive outcomes after immediate primary phacoemulsification for acute primary angle closure.

This study investigated the refractive outcomes of 64 eyes overall including 32 immediate primary phacoemulsification in acute primary angle closure (APAC) eyes and 32 of their fellow eyes. We investigated best-corrected visual acuity, intraocular pressure (IOP), average keratometric diopter (K), spherical equivalent, axial length (AL), central corneal thickness, and anterior chamber depth (ACD) at preoperative examination (Pre) and more than 1-month post-phacoemulsification (1 m), and changes in values. Using SRK/T, Barrett Universal II (Barrett), Hill-Radial Basis Function Version 3.0 (RBF 3.0), and Kane formulas, we calculated and compared refractive prediction error (PE), absolute value of PE (AE), and changes in K, AL, and ACD from Pre to 1 m between APAC and fellow eyes. From Pre to 1 m, K remained similar in APAC and fellow eyes (p = 0.069 and p = 0.082); AL significantly decreased in APAC and in fellow eyes (both p < 0.001); and ACD significantly increased in APAC and in fellow eyes (both p < 0.001). The change in AL differed significantly between the two groups (p = 0.007). Compared to the fellow eyes, PE with SRK/T and Barret formulas (p = 0.0496 and p = 0.039) and AE with Barrett and RBF 3.0 formula (p = 0.001 and p = 0.024) were significantly larger in the APAC eyes. Thus, attention should be paid to refractive prediction error in immediate primary phacoemulsification for APAC eyes caused by preoperative AL elongation due to high IOP.

Nelarabine, intensive L-asparaginase, and protracted intrathecal therapy for newly diagnosed T-cell acute lymphoblastic leukaemia in children and young adults (ALL-T11): a nationwide, multicenter, phase 2 trial including randomisation in the very high-risk group.

BACKGROUND: T-cell acute lymphoblastic leukaemia has distinct biological characteristics and a poorer prognosis than B-cell precursor acute lymphoblastic leukaemia. This trial aimed to reduce the rate of radiation and haematopoietic stem-cell transplantation (HSCT) while improving outcomes by adding nelarabine, intensified L-asparaginase, and protracted intrathecal therapy in the Berlin-Frankfurt-Münster (BFM)-type treatment. METHODS: In this nationwide, multicenter, phase 2 trial, we enrolled patients with newly diagnosed T-cell acute lymphoblastic leukaemia (age <25 years at diagnosis) conducted by Japan Children's Cancer Group and Japan Adult Leukemia Study Group. Patients were stratified into standard-risk, high-risk, and very-high-risk groups according to prednisolone response, CNS status, and end-of-consolidation minimal residual disease. We used the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)-BFM-ALL 2000-backbone chemotherapy. Nelarabine (650 mg/m2 per day for 5 days) was given to high-risk and very high-risk patients. All patients received, until the measurement of end-of-consolidation minimal residual disease, an identical therapy schedule, which included the prednisolone pre-phase remission induction therapy with dexamethasone (10 mg/m2 per day, for 3 weeks [for patients <10 years] or for 2 weeks including a 7-day off interval [for patients ≥10 years]) instead of prednisolone, and consolidation therapy added with Escherichia coli-derived L-asparaginase. On the basis of the stratification, patients received different intensities of treatment; L-asparaginase-intensified standard BFM-type therapy for standard risk and nelarabine-added high risk BFM-type therapy for high risk. In the very high-risk group, patients were randomly assigned (1:1) to group A (BFM-based block therapy) and group B (another block therapy, including high-dose dexamethasone) stratified by hospital, age (≥18 years or <18 years), and end-of-induction bone marrow blast percentage of M1 (<5%) or M2 (≥5%, <25%)+M3 (≥25%). Cranial radiotherapy was limited to patients with overt CNS disease at diagnosis (CNS3; >5 white blood cells per µL with blasts) and patients with no evidence of CNS disease received protracted triple intrathecal therapy. Only very high-risk patients were scheduled to receive HSCT. The primary endpoint was 3-year event-free survival for the entire cohort and the proportion of patients with disappearance of minimal residual disease between randomly assigned groups A and B in the very high-risk group. Secondary endpoints were overall survival, remission induction rate, and occurrence of adverse events. 3 years after the completion of patient accrual, a primary efficacy analysis was performed in the full analysis set and the per-protocol set. This study is registered with the Japan Registry of Clinical Trials, jRCTs041180145. FINDINGS: Between Dec 1, 2011, and Nov 30, 2017, of 349 eligible patients (median age 9 years [IQR 6-13]), 238 (68%) were male, and 28 (8%) patients had CNS3 status. 168 (48%) patients were stratified as standard risk, 103 (30%) as high risk, 39 (11%) as very high risk, and 39 (11%) as no risk (patients who had off protocol treatment before risk assessment. The composite complete remission (complete remission plus complete remission in suppression) rate after remission induction therapy was 89% (298 of 335 patients). HSCT was performed in 35 (10%) of 333 patients. With a median follow-up of 5·2 years (IQR 3·6-6·7), 3-year event-free survival was 86·4% (95% CI 82·3-89·7%) and 3-year overall survival was 91·3% (87·7-93·8%). The proportion of minimal residual disease disappearance was 0·86 (12 of 14 patients; 95% CI 0·57-0·98) in group A and 0·50 (6 of 12 patients, 0·21-0·79) in group B. Grade 3 peripheral motor neuropathy was seen in 11 (3%) of 349 patients and sensory neuropathy was seen in 6 (2%) patients. The most common grade 3 or worse adverse event was febrile neutropenia (294 [84%] of 349 patients). Treatment-related death occurred in three patients due to sepsis, gastric perforation, or intracranial haemorrhage during remission induction. INTERPRETATION: The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use. FUNDING: Ministry of Health, Labor and Welfare of Japan, and Japan Agency for Medical Research and Development. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia.

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures.

Three-Year Outcomes of Immediate Primary Phacoemulsification on Acute Primary Angle Closure Eyes and the Fellow Eyes.

Purpose: This study investigated the long-term outcomes (> 3 years) of immediate primary phacoemulsification in eyes with acute primary angle closure (APAC) and in the fellow eyes with shallow anterior chamber to prevent APAC development. Patients and Methods: This is a retrospective study of phacoemulsification for APAC using bilateral eyes. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), and number of IOP-lowering medications at the preoperative examination (Pre), postoperative month 1 (1m), year 3 (3y), and last visit were compared between 14 eyes with APAC and their 14 fellow eyes. The number of corneal endothelial cells (CECs) at Pre and at more than 2 weeks after phacoemulsification was compared. The visual field mean deviation (MD) within 1 year after phacoemulsification and at the last visit was also compared. Results: For APAC eyes, BCVA was significantly improved at 1m, 3y, and at the last visit as compared with Pre (p < 0.05). IOP significantly decreased at 1m, 3y, and at the last visit compared with Pre (p < 0.05). IOP-lowering medication use decreased significantly from Pre to 1m (p < 0.05). The number of CECs was not significantly different between Pre and more than 2 weeks after phacoemulsification. BCVA was significantly worse in APAC eyes than in fellow eyes at Pre (p < 0.05). IOP and the number of IOP-lowering medications were significantly higher in APAC eyes than in fellow eyes at Pre (p < 0.05). Conclusion: Primary phacoemulsification improved visual acuity for APAC eyes and maintained good IOP control without the need for reoperation. Moreover, it preserved the number of CECs for the APAC and fellow eyes in the long term.

[Steroid-refractory gastrointestinal acute graft-versus-host disease treated with vedolizumab and ruxolitinib in a pediatric patient with therapy-related acute myeloid leukemia].

A 12-year-old girl developed Philadelphia chromosome-positive acute myeloid leukemia due to therapy-related myelodysplastic syndrome with monosomy 7 following neuroblastoma treatment. She underwent allogenic bone marrow transplantation from a human leukocyte antigens-DR1 locus-mismatched unrelated donor. However, on day 49 post transplantation, she presented with diarrhea due to gastrointestinal acute graft-versus-host disease (aGVHD), and treatments with prednisolone, budesonide rectal foam, and human mesenchymal stem cells were ineffective. Therefore, vedolizumab was administered from day 100, which improved the symptoms from gut stage 3 to gut stage 1. Consequently, prednisolone was withdrawn without any serious adverse effects. However, the symptoms worsened to gut stage 3 again; therefore, ruxolitinib was administered to achieve complete remission. Vedolizumab exhibits gut-selective action without systemic immunosuppressive activity. Hence, vedolizumab administration before other systemic immunosuppressive agents may be recommended in patients with steroid-refractory gastrointestinal aGVHD. Thus far, only a few reports have been published regarding the administration of vedolizumab and ruxolitinib for steroid-refractory gastrointestinal aGVHD in children. Further evidence should be obtained from patients treated with vedolizumab and ruxolitinib to confirm their effectiveness for pediatric steroid-refractory gastrointestinal aGVHD.