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ObjectivesWe aimed to describe Familial Hemophagocytic Lymphohistiocytosis (F-HLH) patients' clinical features, intensive care courses, and outcomes.MethodsMulti-center retrospective cohort study of pediatric patients diagnosed with F-HLH from 2015 to 2020 in five tertiary centers in Saudi Arabia. Patients were classified as F-HLH based on their genetic confirmation of known mutation or on their clinical criteria, which include a constellation of abnormalities, early disease onset, recurrent HLH in the absence of other causes, or a family history of HLH.ResultsFifty-eight patients (28 male, 30 female), with a mean age of 21.0 ± 33.9 months, were included. The most common principal diagnosis was hematological or immune dysfunction (39.7%), followed by cardiovascular dysfunction in 13 (22.4%) patients. Fever was the most common clinical presentation in 27.6%, followed by convulsions (13.8%) and bleeding (13.8%). There were 20 patients (34.5%) who had splenomegaly, and more than 70% of patients had hyperferritinemia >500 mg/dl, hypertriglyceridemia >150 mg/dl and hemophagocytosis in bone marrow biopsy. Compared to deceased patients 18 (31%), survivors had significantly lower PT (p = 041), bilirubin level of p = 0.042), higher serum triglyceride level (p = 0.036), and lesser bleeding within the initial 6 h of admission (p = 0.004). Risk factors for mortality included requirements of higher levels of hemodynamic (61.1% vs. 17.5%, p = 0.001) and respiratory (88.9% vs. 37.5%, p p = 0.046).ConclusionsFamilial HLH still represents a challenge in the pediatric critical care setting. Earlier diagnosis and prompt initiation of appropriate treatment could improve F-HLH survival.

Background: Few preclinical models of appendiceal adenocarcinomas (AAs) exist. Orthotopic patient-derived xenografts (PDXs) better recapitulate the original tumor microenvironment. Therefore, we hypothesized that AA patient tumors should grow more successfully in orthotopic PDXs compared to standard flank implanted PDXs. Methods: After obtaining informed consent, tumor samples were obtained from 16 patients with AA undergoing surgical resection at MD Anderson Cancer Center. Tumors were implanted in both the flank and peritoneum of NSG mice; from each patient, at least 6 mice (n≥3 IP, n≥3 flank) were implanted with an approximately 0.5 cm3 tumor. Mice were assessed after 6 months for tumor formation. Whole transcriptomic RNAseq was performed on tumor samples taken from either the flank (n=3) or peritoneum (n=3) of two poorly differentiated (grade 3) patient tumors. The R package DESeq2 was used to conduct differential gene expression analysis comparing IP to Flank PDXs, controlling for the specific patient tumor. Finally, Gene Set Enrichment Analysis (GSEA) with the hallmark gene sets from MSigDB was implemented to study the relative up/down-regulation patterns of gene sets in each PDX cohort. Results: Tumor formation rate, regardless of grade, was greater in IP vs. flank implantation (31.4% vs 11.7%). Higher grade was associated with higher average tumor formation rates (IP—G1: 13.3%, G2: 33.8%, G3: 44.5%; Flank—G1: 0%, G2: 0%, G3: 31.2%). GSEA identified that cell proliferation and energy metabolism gene sets were significantly enriched in IP tumors relative to flank: E2F Targets, G2M Checkpoint, Oxidative Phosphorylation, MYC Targets V1, MYC Targets V2, and DNA Repair (NES = 2.91, 2.62, 2.60, 2.31, 1.61, 1.82, respectively; FDR q-val ≤ 0.01 for all). Meanwhile, gene sets associated with tumor environmental stress were enriched in flank tumors: Angiogenesis, Hypoxia, and TGF-β Signaling (NES = -2.00, -1.73, -1.62, respectively; FDR q-val ≤ 0.01 for all). Epithelial Mesenchymal Transition and TNF-α signaling via NF-κB were also enriched in flank tumors (NES = -2.28, -2.20; FDR q-val < 0.01). Conclusions: The peritoneal microenvironment promotes growth of appendiceal tumors in PDXs, with higher-grade being associated with greater tumor formation rate. GSEA also suggests that AAs preferentially grow in the peritoneal microenvironment in association with greater activation of cellular proliferation and energy metabolism pathways and lower activation of tumor environmental stress pathways. Citation Format: Vinay K. Pattalachinti, Ichiaki Ito, Saikat Chowdhury, Abdelrahman Yousef, Yue Gu, Keith F. Fournier, John P. Shen. Peritoneal microenvironment promotes appendiceal adenocarcinoma tumor formation in PDX models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6546.

Reducing the hazards of the early-onset neonatal sepsis (EONS) is a priority justifying the further investigation for potential biomarkers for its early diagnosis.We aimed to investigate the diagnostic value of presepsin, procalcitonin, lactoferrin, interleukin (IL)-6, and IL-8 for the early diagnosis of EONS.A prospective comparative study, including 30 cases with highly suspected EONS and 30 matched controls, was conducted. Besides the complete blood count and blood culture, C-reactive protein, procalcitonin, presepsin, IL-6, IL-8, and lactoferrin were measured at the admission and after 72 hours.At the time of the admission, presepsin, procalcitonin, C-reactive protein, and IL-8 were significantly higher in the sepsis group. The levels of presepsin, procalcitonin, and IL-8 significantly decreased after 72 hours of the admission. Presepsin, procalcitonin, IL-8, and IL-6 showed a high diagnostic ability for sepsis at admission with area under the curve of 0.934, 0.798, 0.775, and 0.751, respectively. The cutoff values of presepsin, procalcitonin, IL-8, and IL-6 were 821 pg/mL, 2.3 ng/mL, 54 pg/mL, and 24 pg/mL, with a sensitivity of 88.9%, 72.2%, 83.3%, and 94.4% and specificity of 85.7%, 80.9%, 71.4%, and 52.4%, respectively. Lactoferrin had the lowest diagnostic ability with area under the curve of 0.558.Presepsin was the most accurate biomarker followed by procalcitonin, IL-8, and IL-6 regarding the early diagnosis and management of EONS. The combination between these biomarkers is highly recommended.Further studies are needed to investigate the diagnostic ability of the combination of these biomarkers.