Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia

The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRαβ+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease

Cytomegalovirus myelitis in perinatally acquired HIV

A 7 year old child perinatally infected with HIV who died from progressive muscular paralysis and central nervous respiratory failure is described. Cytomegalovirus (CMV) prophylaxis with a special intravenous CMV hyper-immunoglobulin had been successfully conducted for more than four years. Macroscopic and microscopic immunohistochemical examination of the spinal cord revealed a diffuse CMV infiltration of the entire myelon. CMV infected cells were identified as astrocytes, oligodendrocytes, neurons, macrophages, ependymal, endothelial, and Schwann cells. Other organs had no signs of CMV infection. Central nervous spinal CMV infection was most probably due to insufficient penetration of the blood-brain barrier by the CMV hyper-immunoglobulin. In suspicious cases early spinal magnetic resonance imaging (1.5 tesla) combined with an examination of urine and cerebrospinal fluid for CMV is recommended

Prognostic value of 18F-FDG PET/CT for identifying high- and low-risk endometrial cancer patients

Objectives: To assess the usefulness of adding PET/CT as a preoperative test for determining the extent of endometrial cancer and discriminating low- and high-risk patients to identify candidates for surgical staging. Material and methods: We retrospectively reviewed 86 patients with pathologically proven endometrial cancer who had undergone preoperative 18F-FDG PET/CT. The prognostic relationships between PET/CT parameters and pathology reports were assessed. Results: The SUVmax was significantly higher in patients with FIGO stage IB or higher compared with those with stage IA; for stage III–IV compared with stage I–II; and for patients with lymph node metastasis compared with those without lymph node metastasis. Using 6.70 as a cut-off for SUVmax, low-risk patients can be identified with a sensitivity of 92.9%. Conclusions: PET/CT imaging can be used not only for determining malignancy and lymph node involvement but also for determining candidates for surgical staging with high sensitivity

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia—A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis. Keywords: allogeneic hematological stem cell transplantation; antibiotic prophylactic therapy; children; infection precaution; vaccination

Prolonged Pediatric Extracorporeal Membrane Oxygenation Support with Cardiopulmonary Failure in Juvenile Myelomonocytic Leukemia

We report a case of a child survival after extracorporeal membrane oxygenation (ECMO) support of 25 days for cardiopulmonary failure and septic shock in the context of juvenile myelomonocytic leukemia (JMML). ECMO support is still a matter of debate for the management of septic patients with malignancy. However, these patients are at increased risk for early death secondary to pulmonary complications due to leukostasis, direct pulmonary infiltration with WBC, and systemic inflammatory response syndrome following malignant cell lysis. Despite the high risk of complications, ECMO support must be discussed as part of management, providing better outcome in this group of patients