Peripheral expansion of Vδ1-Jδ1/Jδ2+γδT cells and large granular lymphocytes in a patient with Wiskott-Aldrich syndrome

A 7 month old Japanese boy was diagnosed to have Wiskott-Aldrich syndrome (WAS) because of eczema, thrombocytopenia, progressive immune defect and CD43 (sialophorin) abnormality. He had developed repeated infections since 16 months of age. γδT cell-receptor positive T cells in the peripheral blood were gradually increased from 3.1% (7 months of age) to 5.6% (12 months), 19.6% (18 months) and 56.7% (25 months). The phenotypes of expanded γδT cells were δTCS1-positive (Vδ1-Jδ1/Jδ2) and CD8 dim-positive. The proportion of increased granular lymphocytes correlated well with that of γδT cells. The significance of peripheral expansion of γδT cells and granular lymphocytes in WAS is discussed.     

Comparison of outcomes after HLA‐matched unrelated and αβ T‐cell‐depleted haploidentical hematopoietic stem cell transplantation for children with high‐risk acute leukemia

T‐cell‐depleted HAPLO HSCT is an option to treat children with high‐risk acute leukemia lacking an HLA‐identical donor. We reviewed the outcome of children with acute leukemia after HAPLO (n = 21) and HLA‐MUD (n = 32) transplantation. The proportion of patients with ≥CR2 was significantly higher in HAPLO transplantation than MUD transplantation. Patients with MUD transplantation were significantly higher ABO incompatible than patients with HAPLO transplantation. There was no difference between the 2 groups in terms of engraftment, aGvHD and cGvHD, VOD, hemorrhagic cystitis, infections, and relapse. The 5‐year OS of MUD transplantation and HAPLO transplantation groups was found 65.8% and 71.1%, respectively (log‐rank 0.51). The 5‐year RFS was 80.7% for MUD transplantation group and 86.9% for HAPLO transplantation group (log‐rank 0.48). There was no statistically significant difference between 2 groups according to TRM (25% MUD transplantation vs 16.3% HAPLO transplantation, log‐rank 0.48). These data suggest that survival for patients with high‐risk acute leukemia after HAPLO transplantation with ex vivo ɑβ⁺ T‐cell depletion is comparable with MUD transplantation.     

Control of graft‐versus‐host disease with rabbit anti‐thymocyte globulin,rituximab, and bortezomib in TCRαβ/CD19‐depleted graft transplantation for leukemia in children: a single‐center retrospective analysis of two GVHD‐prophylaxis regimens

Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD‐prophylaxis regimens: 35 patients received “Regimen 1” (horse ATG, tacrolimus, and methotrexate) and 46 “Regimen 2” (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6‐23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRαβ/CD19‐depleted transplants between May 2012 and October 2016, from 40 HLA‐matched unrelated and 41 haploidentical donors. After a median follow‐up of 3.9 years, the CI of acute GVHD II‐IV was 15% (95% CI: 7‐30) in the “Regimen 2” group and 34% (95% CI: ?54) in the “Regimen 1” group, P = .05. “Regimen 2” was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2‐19) vs 31% (95% CI: 19‐51), P = .005. The CI of relapse at 3 years adjusted for the GVHD‐prophylaxis regimen groups 31% (95% CI: 19‐51) for the “Regimen 1” vs 21% (95% CI: 11‐37) for the “Regimen 2”, P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti‐leukemic activity.     

Selective T cell‐depleted haploidentical hematopoietic stem cell transplantation for relapsed/refractory neuroblastoma

Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft‐versus‐NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T‐cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49‐11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T‐cell depletion (CD3/CD19‐depletion=1; TCR‐αβ/CD19‐depletion=4; CD3/CD45RA‐depletion=4; and TCR‐αβ/CD45RA‐depletion=1). Conditioning regimens were fludarabine‐based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 10⁹/L) on median D + 8 (range: D + 5 to D + 14). Early T‐ and NK‐cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor‐chimerism post‐HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T‐cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB.     

T-Lymphocytes bearing the γδ T-cell receptor in cutaneous lesions of langerhans' cell histiocytosis

The aim of this study was to investigate the regional importance of γδ T cells in cutaneous lesions of Langerhans' cell histiocytosis. Six cases of Langerhans' cell histiocytosis were investigated by immunohistochemical techniques (alkaline phosphatase-antialkaline phosphatase complex and indirect immunoperoxidase). Increase of γδ T cells was observed in 3 cases of Langerhans' cell histiocytosis. In these cases up to 30% of CD3⁺ cells stained with an anti-TCR γδ monoclonal antibodies and in two of them γδ T cells showed a marked epidermotropism. In the specimens of the remaining three cases γδ T cells were found in an overall percentage of 5% of CD3⁺ cells, but in two cases a significant increase of epidermal γδ T cells was observed. The finding of numerous γδ T cells in Langerhans' cell histiocytosis is provocative and supports the suggestion of a functional relationship between γδ T cells and LCH cells. © 1993 Wiley-Liss, Inc.     

Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation – A comparison of the last two decades

Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992–2002 (P1) and 2003–2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three‐yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT.     

Allogeneic hematopoietic stem cell transplantation for Chediak–Higashi syndrome

The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC‐HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease.     

Meta‐analysis of hematopoietic stem cell transplantation in major histocompatibility complex class II deficiency

Major histocompatibility complex class II deficiency is a rare case of PID. Specific recommendations for hematopoietic stem cell transplant, the only curative treatment option, are still lacking. This meta‐analysis aims to identify the factors associated with better prognosis in these patients. Thirteen articles reporting 63 patients with major histocompatibility complex class II deficiency that underwent hematopoietic stem cell transplant were included. The median age for hematopoietic stem cell transplant was 18 months. The most common source of transplant was bone marrow, with alternative sources as umbilical cord blood emerging during recent years. The highest proportion of engraftment was seen with umbilical cord. Engraftment was higher in patients with matched donors, with better overall survival in patients with reduced‐intensity conditioning. Graft‐vs‐host disease developed in 65% of the patients, with grades I‐II being the most frequently encountered. There was a higher mortality in patients with myeloablative conditioning and no engraftment. There was an inverse correlation between survival and stage of graft‐vs‐host disease. The main cause of mortality was infectious disease, mostly secondary to viral infections. Ideally, matched grafts should be used, and reduced‐intensity conditioning should be considered to reduce early post‐transplant complications. GVHD and viral prophylaxis are fundamental.     

Evaluation of proximal tubular function in preterm infants by urinary α1-microglobulin

α₁-Microglobulin is a low molecular weight protein that is relatively stable in urine of low pH. There have been few reports on urinary α₁-microglobulin (U-A₁M) excretion in preterm infants. This study was designed to establish the ranges for U-A₁M in clinically stable preterm infants and to investigate changes observed in sick preterm infants. We measured U-A₁M and urinary β₂-microglobulin (U-B₂M) levels at 1, 4, 7, 14, 28 and 90 days after birth in stable preterm infants (Group 1) and sick preterm infants who were depressed at birth and required immediate resuscitation (Group 2). In Group 1 infants, both parameters were high during the first 28 days and appeared to decline thereafter. U-A₁M in Group 2 infants was only significantly increased compared with Group 1 on day 1, as was U-B₂M. On each day of the study, U-A₁M had significant positive correlations with U-B₂M for all the infants studied. The changes of the two parameters observed in Group 1 probably reflect postnatal evolution of proximal tubular function in stable preterm infants. A comparison of groups 1 and 2 shows a high prevalence of acute tubular injury at birth in sick infants and also suggests that U-A₁M as well as U-B₂M may be a sensitive index for detecting acute tubular damage and for following its course in preterm infants.     

Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation

Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopietic stem cell transplantation.
Pediatr Transplantation 2012: 16: E39–E42. © 2010 John Wiley & Sons A/S. Abstract: TA‐TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA‐TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA‐TMA after allogeneic HSCT.     

Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes

Elder DA, Woo JG, D’Alessio DA. Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes. Background: Adults with type 2 diabetes mellitus (T2DM) have broad impairments in β‐cell function, including severe attenuation of the first‐phase insulin response to glucose, and reduced β‐cell mass. In adolescents with T2DM, there is some evidence that β‐cell dysfunction may be less severe. Our objective was to determine β‐cell sensitivity to glucose and maximal insulin secretory capacity (AIR_max) in teenagers with T2DM. Methods: Fifteen adolescents with T2DM [11 F/4 M, age 18.4 ± 0.3 yr, body mass index (BMI) 39.8 ± 2.2 kg/m²] and 10 non‐diabetic control subjects (7 F/3 M, age 17.4 ± 0.5 yr, BMI 41.5 ± 2.2 kg/m²) were studied. T2DM subjects had a mean duration of diabetes of 48.8 ± 6.4 months, were treated with conventional therapies, and had good metabolic control [hemoglobin A1c (HbA1c) 6.7 ± 1.2%]. Insulin and C‐peptide were determined before and after a graded glucose infusion and after intravenous arginine at a whole blood glucose level of ≥22 mM. Results: The insulin response to increasing plasma glucose concentrations was blunted in the diabetic compared with control subjects (34.8 ± 11.9 vs. 280.5 ± 57.8 pmol/mmol; p < 0.0001), and AIR_max was also significantly reduced in the diabetic group (1868 ± 330 vs. 4445 ± 606; p = 0.0005). Conclusion: Even adolescents with well‐controlled T2DM have severe impairments of insulin secretion. These data support β‐cell dysfunction as central in the pathogenesis of T2DM in young people, and indicate that these abnormalities can develop over a period of just several years.     

Chemotherapy and interferon‐α treatment of Erdheim–chester disease

Erdheim–Chester disease (ECD) is a rare non‐Langerhans cell histiocytosis of an unknown origin. The prognosis of ECD is variable, and it mainly depends on the involved anatomic sites. The treatment modalities have not been standardized. Interferon‐α (IFN) has been reported to be effective in the management of ECD. We report here on an uncommon case with ECD in a 17‐year‐old female who had multiple lesions in the whole body and she was treated with chemotherapy and IFN. She has remained disease‐free for 2 years after the completion of treatment. Pediatr Blood Cancer. 2010;55:745–747. © 2010 Wiley‐Liss, Inc.