Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia?

BACKGROUND: Repeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities. METHODS: Thirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m2 were used for low-risk patients and 5 g/m2 for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX24) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL. RESULTS: The patients' age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3-4 anemia, grades 3-4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003, p=0.007, p=0.006, and p=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m2 than the 5 g/m2 HDMTX cycles (46.7 vs. 26.7%, p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m2 HDMTX cycles (median= 7 days vs. 4 days, p=0.012). CONCLUSIONS: Serum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities.

CHRIST: CD44-Incorporated Hepatocellular Carcinoma Risk Index Scoring Tool-A Novel Prognostic Scoring System for Hepatocellular Carcinoma Development and Aggressiveness.

CD44 has been demonstrated to play a pivotal role in regulating tumor cell progression, including hepatocellular carcinoma (HCC) development. Here, we aimed to establish a scoring system to evaluate the risk of developing HCC utilizing CD44-rs187115 SNP polymorphism. A prospective cohort of 120 individuals was enrolled in four groups: 19 non-metastatic HCC patients, 21 metastatic, 40 patients with hepatitis C-related cirrhosis, and 40 controls. Allelic discrimination of the CD44-rs187115 gene polymorphism was assessed using TaqMan genotyping assay. HCC patients with CT/CC genotypes were more likely to have aggressive malignancy compared to TT carriers. A significant correlation was noted between the existence of CT/CC genotypes and tumor size, multicentricity, infiltration, portal vein thrombosis, and metastasis. A CD44-incorporated Hepatocellular Carcinoma Risk Index Scoring Tool (CHRIST) was formulated utilizing clinical and genetic variables. A score > 3 for HCC development demonstrated 87.5% sensitivity, 72.5% specificity, and a 76% positive predictive value (PPV) and 85% negative predictive value (NPV). Furthermore, a score > 5 for HCC metastasis demonstrated 90.4% sensitivity, 68.4% specificity, a 76% PPV and 86% NPV. A similarly significant score was noted following a six-month re-evaluation. We conclude that CD44-rs187115 may serve as a reliable prognostic biomarker for HCC and that the CHRIST prognostic model is highly predictive of the development of HCC and metastatic HCC.

Serum and ascitic D-dimer in cirrhotic patients with spontaneous bacterial peritonitis.

AIM OF THE STUDY: The study aimed to investigate serum and ascitic fluid D-dimer level in patients with liver cirrhosis with and without ascites and to evaluate the impact of spontaneous bacterial peritonitis (SBP) on circulating serum and ascitic fluid D-dimer levels. MATERIAL AND METHODS: This study was conducted on 60 subjects who were further subdivided into group I comprising 15 patients with liver cirrhosis and no ascites, group II comprising 15 cirrhotic patients with ascites, group III comprising 15 cirrhotic patients with ascites and SBP, and group IV comprising 15 healthy controls. All patients were subjected to full history taking, physical examination, laboratory investigations, and measurement of serum D-dimer in all groups and ascitic fluid D-dimer in groups II and III. The diagnostic performance of serum D-dimer was tested to detect SBP. RESULTS: Serum D-dimer differed significantly between groups III and IV, whilst no significant differences were detected between the other groups and group IV. Moreover, group III showed a significantly higher level of serum D-dimer. Ascitic fluid D-dimer mean levels showed no statistically significant differences. A statistically significant positive correlation was found between serum D-dimer level and ascitic fluid D-dimer in group III, r = 0.682. Using a sensitivity and specificity level of 80%, a cut-off value (COV) of > 323.2 ng/ml could differentiate between patients with SBP and patients with ascites only. CONCLUSIONS: Serum D-dimer significantly correlated with ascitic fluid D-dimer in patients with SBP, whereas no significant correlation was found in patients with cirrhotic ascites without bacterial infection. D-dimer showed good diagnostic performance for SBP among patients with liver cirrhosis.

Clinical Characteristics and Outcomes of 101 Children with Hemophagocytic Lymphohistiocytosis: A Four-Year Single-Center Experience from Egypt.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, arising either due to genetic mutations or from a variety of underlying diseases. This prospective observational study reports the clinical and laboratory data as well as the outcome of pediatric HLH in Egypt. HLH was diagnosed according to the Histiocyte Society HLH-2004 diagnostic criteria conducted at Alexandria University Children's Hospital over four years. One-hundred-one patients were enrolled (44 males and 57 females), and the median age at presentation was 13.1 months (range: 1 day - 181.4 months). Almost 75% of the patients had consanguineous parents, and one-third had a history of an affected family member (HLH or HLH-like illness). The median time interval between the first HLH symptom and diagnosis was 34 days. At diagnosis, patients were preliminarily classified as having primary HLH in 61% of patients and secondary HLH in 39% of patients. The diagnosis was confirmed genetically in 57 patients. Seventy-eight percent of patients received the HLH-94 and HLH-2004 protocols, only seven patients have undergone hematopoietic stem cell transplantation. The overall survival was 26.4% by the end of the study; the most common cause of death was uncontrolled disease activity. This descriptive study, on a large cohort of pediatric HLH in Africa and the Middle East, sheds some light on the epidemiological characteristics of HLH patients and the available diagnostic and therapeutic tools. The mortality rate was considerably high, highlighting the importance of early diagnosis and initiation of appropriate therapy.

Impact of CD44 gene single nucleotide polymorphism (rs 13347) in mobilization of autologous HSCT.

MOBILIZATION: of stem cells into peripheral blood is a crucial step in the procedure of autologous stem cell transplantation. Mobilization can be affected by many variables;underlying diseases, prior treatment and age. Many genetic polymorphisms mainly in adhesion molecules are thought to affect mobilization success. The CD44 is a cell adhesion molecule which is highly heterogeneous structurally. Polymorphisms in this molecule may impair HSC lodgment in the bone marrow. THE AIM OF THE WORK: was to assess the impact of CD44 single nucleotide polymorphism (rs13347) on the efficacy of mobilization of CD34+ hematopoietic progenitor cells in a cohort of Egyptian patients treated for lymphoma and multiple myeloma and scheduled for autologous stem cell transplantation. PATIENTS AND METHODS: the study was conducted on 92 patients scheduled for autologous HSC mobilization and transplantation. SNP genotyping was done by 5 ꞌ nuclease assay on rotor gene. RESULTS: A statistical significant difference was detected between the patients with genotypes (CT + CC) and patients with (TT) genotype regarding the number of apheresis sessions required to gather the target CD34 count (p = 0.006).T allele is implicated in poorer mobilization. CONCLUSIONS: CD44 SNPs analysis may be helpful for predicting the poor mobilizers. These patients may benefit from newer modalities like adhesion molecules inhibitors.

Evaluation of multiplexed biomarkers in assessment of CSF infiltration in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a very common pediatric malignancy with high survival rates. The course of treatment is modified according to the occurrence of central nervous system (CNS) disease. Aim: To relate serum and cerebrospinal fluid levels of five biomarkers (matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10) at diagnosis to the development of CNS infiltration. Methods: The present study was carried on 64 children with ALL and 20 controls. Multiplexed cytokines were measured by Luminex technology (Matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10). Results: Significantly higher sMMP-9 and lower sCCL2 were found in patients who developed CNS leukemia. Conclusion: Serum multiplexed parameters at diagnosis of childhood ALL may predict of development of CNS leukemia.

Clinical significance of T cell receptor excision circle (TREC) quantitation after allogenic HSCT.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of diseases. Immune reconstitution is an important event that determines outcomes. The immune recovery of T cells relies on peripheral expansion of mature graft cells, followed by differentiation of donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. The aim of this study was to determine the role of TREC quantitation in predicting outcomes of human leucocyte antigen (HLA) identical allogenic HSCT. METHODS: The study was conducted on 100 patients receiving allogenic HSCT from an HLA identical sibling. TREC quantification was done by real time PCR using a standard curve. RESULTS: TREC levels were inversely related to age (P=0.005) and were significantly lower in patients with malignant diseases than in those with benign diseases (P=0.038). TREC levels could predict relapse as an outcome but not graft versus host disease (GvHD) and infections. CONCLUSION: Age and nature of disease determine the TREC levels, which are related to relapse.