Outcomes of HLA-mismatched HSCT with TCRαß/CD19 depletion or post-HSCT cyclophosphamide for inborn errors of immunity.

ABSTRACT: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αß/CD19 (TCRαß) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαß (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαß and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαß and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαß (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαß, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαß and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαß 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαß. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.

Portal vein thrombosis in a child with essential thrombocythemia seven years after diagnosis.

Portal vein thrombosis in children with essential thrombocythemia (ET) is a rarity. Here, we describe the long-term follow up of our previously reported case that since has developed portal vein thrombosis (PVT) 7-years after diagnosis. Our patient had presented with PVT with normal platelet counts and massive asymptomatic splenomegaly. Ultrasound and Computerized tomography confirmed presence of PVT. Our case highlights the importance of long-term follow up of children with ET for thrombosis, especially PVT, as it can happen without symptoms and normal platelet counts.

Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders.

We describe here the outcomes of reduced-toxicity alternate-donor stem cell transplant (SCT) with posttransplant cyclophosphamide (PTCy) for primary immunodeficiency disorders (PIDs) in eight children (haploidentical-seven and matched unrelated donor-one). The conditioning was with serotherapy (alemtuzumab-3/rabbit-anti-thymoglobulin-5); fludarabine, cyclophosphamide, and total body irradiation-5 (additional thiotepa-3); fludarabine and treosulfan-2; and fludarabine and busulfan-1. All received PTCy 50 mg/kg on days 3 and 4 as graft versus host disease prophylaxis along with tacrolimus and mycophenolate. Mean CD34 dose was 13.8 × 106 /kg. Two children died because of PIDs. Acute graft versus host disease up to grades I and II was seen in three children. All six survivors are fully donor and disease free at median follow-up of 753 days. Alternate donor SCT with PTCy is feasible in PID and has good outcomes.

Structure and binding studies of proliferating cell nuclear antigen from Leishmania donovani.

Proliferating cell nuclear antigen (PCNA) acts as a sliding clamp to support DNA replication and repair. The structure of PCNA from Leishmania donovani (LdPCNA) has been determined at 2.73Å resolution. Structure consists of six crystallographically independent molecules which form two trimeric rings. The pore diameter of the individual trimeric ring is of the order of 37Å. The two rings are stacked through their front to front faces. In order to gain a stable packing, the rings are rotated by 42° about the pore axis and shifted by 7Å and tilted by 16° along the perpendicular direction to pore axis. This form of stacking reduced the effective diameter of the pore to 32Å. The sequence of LdPCNA consists of a long segment of 41 amino acid residues (186-Gly-Val-Ser-Asp-Arg-Ser-Thr-Lys-Ser-Glu-Val-Lys-Ala-Glu-Val-Lys-Ala-Glu-Ala-Arg-Asp-Asp-Asp-Glu-Glu-Pro-Leu-Ser-Arg-Lys-Tyr-Gly-Lys-Ala-Asp-Ser-Ser-Ala-Asn-Ala-Ile-226) whereas the corresponding segments in other PCNAs contain only eight residues corresponding to 186-Gly-Val-Ser-Asp-Arg------224-Asn-Ala-Ile-226. The enhanced length of this segment in LdPCNA may influence its mode of interaction with DNA and other proteins. The dissociation constants obtained using real time binding studies with surface plasmon resonance (SPR) for two peptides, Lys-Arg-Arg-Gln-Thr-Ser-Met-Thr-Asp-Phe-Tyr-His (P1) from human cyclin-dependent kinase inhibitor-1(CKI-1) and Lys-Thr-Gln-Gly-Arg-Leu-Asp-Ser-Phe-Phe-Thr-Val (P2) from flap endonuclease 1 (Fen-1) as well as with two small molecule inhibitors, (S)-4-(4-(2-amino-3-hydroxypropyl)-2, 6-diiodophenoxy) phenol hydrochloride (ADPH) and N-(3-methylthiophene-2-carboxylicacid)-N'-((3-hydroxy-2-naphthalenyl) methylene) hydrazide (MCMH) are 0.29±0.09µM, 0.37±0.08µM, 0.35±0.09µM and 1.20±0.08µM respectively. The corresponding values obtained using fluorescence spectroscopic methods were 0.22±0.06µM, 0.68±0.07µM, 0.44±0.07µM and 0.75±0.05µM respectively.

Primary immunodeficiency disorders in the developing world: data from a hospital-based registry in India.

Primary immunodeficiency disorders (PID) are under-reported from the developing world. We present data regarding diagnosis and outcome from a hospital-based registry in India. Forty-seven patients fulfilled diagnostic criteria. Majority were males. Subgroups were disorders of immune dysregulation-29%, B&T-cell abnormalities-28%, predominant antibody deficiencies-23%, other well-defined immunodeficiencies-15%, and phagocyte disorders-4%. Molecular diagnosis was attempted in 12 and was positive in seven. Overall 24 children died. Only three out of 28 children needing stem cell transplant (SCT) underwent the same. Registry data highlights that molecular diagnosis and SCT are a rarity for children with PIDs in the developing world and mortality is high.

Hemophagocytic lymphohistiocytosis in infants: a single center experience from India.

There is paucity of outcome data for hemophagocytic lymphohistiocytosis (HLH) in infants from India, especially post stem cell transplant (SCT). We report outcome data of eight infants diagnosed with HLH. Mean age was 7.1 months (range 2-11). Mutation analysis was possible in seven patients. One patient had Griscelli syndrome. In three patients, no known mutation could be identified, while in remaining three homozygous mutations in Perforin, Munc and STX11 gene were identified. All were treated as per HLH 2004 protocol. Four died during induction phase. One patient abandoned therapy. Two underwent SCT, while one is awaiting SCT. First patient is alive and disease-free at 22 months postmatched sibling donor SCT. Second underwent unrelated double cord blood transplant, but died 5 months posttransplant due to renal failure. It is feasible to offer SCT for infants with familial HLH in the developing world although barriers like sepsis and disease refractoriness remain.

Barriers to cure for children with cancer in India and strategies to improve outcomes: a report by the Indian Pediatric Hematology Oncology Group.

The survival of children with cancer in India is inferior to that of children in high-income countries. The Indian Pediatric Hematology Oncology Group (IPHOG) held a series of online meetings via www.Cure4kids.org to identify barriers to cure and develop strategies to improve outcomes. Five major hurdles were identified: delayed diagnosis, abandonment, sepsis, lack of co-operative groups, and relapse. Development of regional networks like IPHOG has allowed rapid identification of local causes of treatment failure for children with cancer in India and identification of strategies likely to improve care and outcomes in the participating centers. Next steps will include interventions to raise community awareness of childhood cancer, promote early diagnosis and referral, and reduce abandonment and toxic death at each center. Starting of fellowship programs in pediatric hemato-oncology, short training programs for pediatricians, publishing outcome data, formation of parent and patient support groups, choosing the right and effective treatment protocol, and setting up of bone marrow transplant services are some of the effective steps taken in the last decade, which needs to be supported further.

Intestinal mucormycosis: a rare entity in pediatric oncology.

Mucormycosis is increasingly emerging as an important cause of invasive fungal infection in immunocompromised patients. Intestinal mucormycosis is extremely rare, difficult to diagnose, and has dismal prognosis. We report two children with acute lymphoblastic leukemia and intestinal mucormycosis. Despite surgery and appropriate antifungal therapy, only one survived. Literature review showed only 10 other childhood cancer cases with intestinal mucormycosis. All had abdominal pain preceding gut perforation. All except one had leukemia and majority were in induction phase of therapy. Only 5 of these 12 children survived. Other than appropriate antifungal therapy, early surgery and rising neutrophils aid in recovery.

Physicochemical and bioactive constituents, microbial counts, and color components of spray-dried Syzygium cumini L. pulp powder stored in different packaging materials under two controlled environmental conditions.

Currently, the demand for functional food items that impart health benefits has been rising. Blackberry (Syzygium cumini L.) fruit has high anthocyanin content and other functional attributes. However, this seasonal fruit is highly perishable, and a large proportion of it goes unharvested and wasted worldwide. Spray drying of the fruit pulp can impart improved shelf life, ensuring long-term availability for consumers to exploit its health benefits. The storage quality varies according to the type of packaging material and the storage environment. Therefore, in this study, the shelf life span of the spray-dried Syzygium cumini L. pulp powder (SSCPP) was investigated during 6 months of storage under three types of packaging materials (i.e., polystyrene, metalized polyester, and 4-ply laminates) in a low-temperature environmental (LTE) and at ambient environmental conditions. The physicochemical stability of bioactive principles (TPC and TAC), microbial counts, and color components were analyzed at 0, 2, 4, and 6 months of storage. There was a significant gradual loss of dispersibility and solubility with an increase in flowability, bulk density, and wettability during the entire storage period for all three packaging materials. The TSS, pH, TPC, TAC, and microbial counts decreased in the SSCPP both at ambient and LTE conditions during the study. Among all the packaging materials, the 4-ply laminate was found to be the most appropriate and safe for storage of spray-dried SCPP at LTE conditions.

A comprehensive review on infant formula: nutritional and functional constituents, recent trends in processing and its impact on infants' gut microbiota.

Human milk is considered the most valuable form of nutrition for infants for their growth, development and function. So far, there are still some cases where feeding human milk is not feasible. As a result, the market for infant formula is widely increasing, and formula feeding become an alternative or substitute for breastfeeding. The nutritional value of the formula can be improved by adding functional bioactive compounds like probiotics, prebiotics, human milk oligosaccharides, vitamins, minerals, taurine, inositol, osteopontin, lactoferrin, gangliosides, carnitine etc. For processing of infant formula, diverse thermal and non-thermal technologies have been employed. Infant formula can be either in powdered form, which requires reconstitution with water or in ready-to-feed liquid form, among which powder form is readily available, shelf-stable and vastly marketed. Infants' gut microbiota is a complex ecosystem and the nutrient composition of infant formula is recognized to have a lasting effect on it. Likewise, the gut microbiota establishment closely parallels with host immune development and growth. Therefore, it must be contemplated as an important factor for consideration while developing formulas. In this review, we have focused on the formulation and manufacturing of safe and nutritious infant formula equivalent to human milk or aligning with the infant's needs and its ultimate impact on infants' gut microbiota.

Hepatic hemangioendothelioma in an infant with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a rare disorder caused by heterogeneous genetic mutations. We describe here a rare association of SCN caused by a novel ELANE mutation and infantile hepatic hemangioendothelioma. In a 2-month-old infant, an abdominal ultrasound performed for omphalitis revealed a hepatic tumor, which was resected. Histopathology confirmed the diagnosis of hemangioendothelioma. Postoperatively, severe neutropenia was noted. Bone marrow examination showed myeloid maturation arrest, diagnostic of SCN. Mutation analysis for the neutrophil elastase gene identified a novel heterozygous de novo ELANE missense mutation in exon 2 (c.215T>A, p.Val72Glu). He was managed successfully with broad-spectrum antibiotics and high-dose granulocyte colony-stimulating factor.

Eyelid nodule: a rare presentation of Langerhans cell histiocytosis.

Langerhans cell histiocytosis occurring as an isolated tumor of eyelid has rarely been reported. We report an unusual case of a 5-year-old boy who presented with a smooth nodular lesion over the right lower eyelid accompanied with hyperemia for a month. The biopsy and CD1a positivity confirmed it to be Langerhans cell histiocytosis. It was localized to the eyelid as no other organ was involved. Although Langerhans cell histiocytosis of the eyelid is exceptional, it must be included in the differential diagnosis of eyelid nodular lesions and the diagnostic and the subsequent management must be multidisciplinary.

Effect of Astaxanthin and Copper Supplementation on Growth, Immunity, Antioxidant, and Blood Biochemical Status of Growing Murrah Buffalo Heifers.

This study was aimed to explore the effect of astaxanthin (ASTX) and copper (Cu) supplementation on the growth, immunity, antioxidant, and blood biochemical status of growing Murrah buffalo heifers. Twenty-eight Murrah buffalo heifers were selected and randomly divided into 4 groups (n = 7) after blocking by body weight (BW) (129.86 ± 5.37 kg) and age (9.05 ± 1.02 months). The heifers were fed basal total mixed ration diet without supplementation (CON) or with ASTX (0.20 mg/kg BW; AX), Cu (10 mg/kg DM; CU), or ASTX + Cu (0.20 mg/kg BW + 10 mg/kg DM; AX + CU) for 90 days of study period. The result showed that BW and dry matter intake (DMI) were significantly higher (P < 0.05) in AX + CU than that in other groups. The average daily gain (ADG) and feed conversion efficiency (FCE) were statistically higher (P < 0.05) in treatments than the values observed in CON. The feed conversion ratio (FCR) was reported significantly lower (P < 0.05) in the AX + CU group followed by AX, CU, and CON groups. The total leukocytes count (TLC), lymphocytes, and total immunoglobulin (TIG) were statistically higher (P < 0.05) in AX + CU groups than that found in other groups. However, neutrophil % decreased (P < 0.05) in the AX + CU group than its level in other groups. Superoxide dismutase (SOD), catalase (CAT), and total antioxidant (TAA) levels were observed higher (P < 0.05) in treatments supplemented with ASTX, Cu, or both than CON group. Thiobarbituric acid reactive substance (TBARS) concentration was lower (P < 0.05) in treatments than its level found in the CON group. Glucose level was higher (P < 0.05); however, non-esterifies fatty acid (NEFA) was lower (P < 0.05) in AX + CU than that in others groups. The level of cholesterol (CH), HDL cholesterol (HDL-CH), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were reported lower (P < 0.05) in the AX + CU group followed by CU, AX, and CON groups. The copper (Cu) level was higher (P < 0.05) in CU and AX + CU than AX and CON groups. The result of the present study indicated that the supplementation of ASTX, Cu alone, or their combination improved the growth, immunity, antioxidant status, and liver function of growing heifers.

Wilms tumor with Mulibrey Nanism: A case report and review of literature.

BACKGROUND: Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2-year-old boy with WT and MUL and present a review of literature on WT in MUL. CASE: Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi-speciality care. He is alive and in remission at follow-up of 6 months. CONCLUSION: A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.

Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia.

Heme oxygenase-1 (HO-1) is a stress-induced enzyme that catalyses the oxidation of heme to biliverdin. The primary deficiency of this enzyme has been shown in HO-1 knockout mice, and is characterized by intrauterine death and chronic inflammation. The first case of human HO-1 deficiency was reported in 1999. Human HO-1 deficiency has been observed to involve the endothelial cells more severely, resulting in hemolysis and disseminated intravascular coagulation. We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab.