Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Excellent remission rates with limited toxicity in relapsed/refractory Langerhans cell histiocytosis with pulse dexamethasone and lenalidomide in children.

Refractory/relapsed Langerhans cell histiocytosis (LCH) has a difficult course with a guarded prognosis. We used a novel protocol including six cycles of pulse dexamethasone and lenalidomide in four children with LCH refractory to first-line agents and courses of cladribine and cytarabine or single-agent cladribine. All four children completed the protocol without any significant adverse effects and remain in complete and durable remission 15-18 months posttreatment. The novel protocol we propose for relapsed/refractory LCH is cost-effective and outpatient-based with durable remission and minimal toxicity. This is particularly suited for resource-limited settings.

Combating blood stream infections during induction chemotherapy in children with acute myeloid leukemia: Single center results in India.

Optimal management of infectious complication is the biggest challenge in children receiving chemotherapy for acute myeloid leukemia (AML). We have analyzed the data of children undergoing AML induction chemotherapy at our center from 2002 to 2016 and found that Gram-negative infections are more predominant when compared to the published literature. There also has been a surge in multidrug-resistant (MDR) infections over the last 4 years, which has increased the need for supportive care and escalated the cost of care. We have introduced certain novel methods to combat MDR sepsis and decrease mortality rates.

Cytomegalovirus reactivation posthematopoietic stem cell transplantation (HSCT) and type of graft: A step toward rationalizing CMV testing and positively impacting the economics of HSCT in developing countries.

We aimed to determine a correlation between cytomegalovirus reactivation post hematopoeitic stem cell transplantation (post-HSCT) with the type of graft source, defining children at risk. We analyzed data on children less than 18 years of age undergoing HSCT from 2002 to May 2016 (n = 464). Correlation between reactivation and graft source was analyzed statistically. Reactivation occurred in 3% of children with matched-related donor (MRD) transplants, 33.3% with unrelated peripheral blood stem cells, 17.4% with unrelated cords, and 36.5% (15/41) with mismatched or haploidentical grafts (P = <0.0001). MRD does not warrant weekly PCR, unlike unrelated or haploidentical donors, thus defining protocols for developing countries with limited resources.

Successful Treatment of Refractory Langerhans Cell Histiocytosis of the Choroid Plexus in a Child With Pulse Dexamethasone and Lenalidomide.

Refractory/relapsed Langerhans cell histiocytosis (LCH) has a difficult course with a guarded prognosis. Salvage treatments available are both expensive and highly toxic. On the basis of the pathophysiology of LCH, we used a novel protocol including pulse dexamethasone and lenalidomide in a child with refractory LCH involving the choroid plexus, which resulted in durable remission with minimal toxicity. The protocol was extrapolated from the FIRST trial for patients with multiple myeloma. We present the clinical course, treatment protocol, and outcome in this child, who is at present disease free and in remission 18 months posttreatment.

Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

Introduction: From the advancement of treatment of pediatric cancer diagnosis, the five-year survival rate has increased significantly. However, the adverse consequence of improved survival rate is the second malignant neoplasm. Although previous studies provided information on the incidence and risk of SMN in long term survivors of childhood cancer, there is still scarce information known for short term (< 5 years) prognosis. This study aims to assess the incidence, characteristics, management, and outcome of children who develop SMN malignancies within 5 years of diagnosis of their initial cancer. Method: This is a retrospective cohort study of early Second Malignant Neoplasms (SMN) in pediatric oncology patients. The Cancer in Young People - Canada (CYP-C) national pediatric cancer registry was used and reviewed pediatric patients diagnosed with their first cancer from 2000-2015. Results: A total of 20,272 pediatric patients with a diagnosis of a first malignancy were analyzed. Of them, 0.7% were diagnosed with a SMN within the first 5 years following their first cancer diagnosis. Development of a SMN impacted survival, shown by an inferior survival rate in the SMN cohort (79.1%) after three years compared to that of the non-SMN cohort (89.7%). Several possible risk factors have been identified in the study including the use of epipodophyllotoxins, exposure to radiation, and hematopoietic stem cell 169 transplant. Discussion: This is the first national study assessing the incidence, 170 characteristics, risk factors and outcome of early SMN in Canadian children 171 from age 0-15 from 2000-2015.

Corrigendum: Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

[This corrects the article DOI: 10.3389/fonc.2024.1376652.].

Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia and the Role of MRD: A Single Centre Experience from India.

Hematopoietic stem cell transplantation (HSCT) is an effective curative option for children with relapsed and high risk acute lymphoblastic leukemia (ALL). The effect of minimal residual disease (MRD) prior to transplantation has a significant impact on the overall outcome. We performed a retrospective analysis of children with ALL who underwent HSCT at our centre from 2002 to 2016. From 2002 to 2008 disease status was determined by morphology and karyotyping and from 2008 onwards by flow cytometry. A total of 46 children were transplanted for ALL at our centre. Of the 19 children who were MRD positive prior to HSCT 5 had a relapse after the transplant. Among the remaining 26 MRD negative children, only one child relapsed post HSCT. The EFS was 66.6% in the MRD negative group and 63.1% in positive group with no significant survival advantage of the first group over the second, (p 0.37). GVHD was the major cause of mortality overall at 56.7% as well as in the MRD negative group at 77.7%(7/9). On the other hand, relapse was the major mortality factor at 71.4%(5/7) in the MRD positive group. Molecular remission prior to HSCT shows a trend towards lesser chance of relapse. We should strive to achieve MRD negative status prior to transplant to improve EFS. However, GVHD is also emerging as a crucial factor and its impact on survival outcome in children undergoing HSCT for ALL needs to be followed up.

Changing Trends in the Use of Granulocyte Transfusions in Neutropenic Children with Sepsis in India.

We present our data on granulocyte transfusions in children undergoing treatment for cancer and HSCT at our centre and their changing indications. In this retrospective observational analysis of children who received granulocytes from 2007 to 2015, we divided children receiving granulocytes into two groups-the first from January 2007 till December 2013 and the second from January 2014 till December 2015. This division is based on the change in our policy to use granulocytes within 48 h of septicemia as the incidence of drug resistant bacterial strains had increased at our centre. Data on 72 children with febrile neutropenia treated with 230 granulocyte infusions was analyzed. From 2007 to 2013 (n = 48/72), 27/48 (56 %) had culture proven sepsis of which 14 (51 %) were carbapenem resistant gram negative bacilli. 11 of the 27 children survived the crisis (41 %). We then changed our policy to transfuse granulocytes early during sepsis. From 2014 to 2015 (n = 24/72) 22 patients had culture proven sepsis (91 %) of which 20 had carbapenem resistant gram negative bacilli. 12/22 (54 %) with culture proven sepsis survived the episode. The survival rate improved from 41 % in first group to 54 % after early intervention with granulocytes (P value 0.0347). Despite the increased incidence of resistant bacteria during the period of 2014-2015, early use of granulocytes improved survival rate from 41 to 54 %. This intervention cannot be taken in isolation and needs to be offered early in parallel with appropriate antibiotics.

Kaposiform Hemangioendothelioma in a 3 Months Old Infant.

Kaposiform hemangioendothelioma is a rare, highly vascular and aggressive soft tissue tumor frequently associated with Kasabach-Merritt phenomenon, usually seen in early infancy. Early diagnosis by means of MRI and tissue biopsy portends a better outcome. Treatment includes surgical excision when feasible and medical management with steroids, propranolol, vincristine and supportive treatment for coagulopathy. We report a 3 months old female infant who was diagnosed, treated successfully and is now in complete remission.